bims-bicyki 2022-02-20 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–02–20
twenty-six papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

AMPK and Polycystic Kidney Disease Drug Development: An Interesting Off-Target Target.
Lessons from microRNA biology: Top key cellular drivers of Autosomal Dominant Polycystic Kidney Disease.
Recurrent thromboses and major vessel compressions in autosomal dominant polycystic kidney disease.
Secreted Neutrophil Gelatinase-Associated Lipocalin Shows Stronger Ability to Inhibit Cyst Enlargement of ADPKD Cells Compared with Nonsecreted Form.
Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use.
Initial decline in eGFR to predict tolvaptan response in autosomal-dominant polycystic kidney disease.
Long-Term Outcomes of Longitudinal Efficacy Study With Tolvaptan in ADPKD.
Reduced expression of TAZ inhibits primary cilium formation in renal glomeruli.
PCD Genes-From Patients to Model Organisms and Back to Humans.
A MRI-based radiomics nomogram for evaluation of renal function in ADPKD.
Oxycodone relieves permeability damage and apoptosis of oxygen-glucose deprivation/reoxygenation-induced brain microvascular endothelial cells through ras homolog family member A (RhoA)/ Rho-associated coiled-coil containing kinases (ROCK)/ myosin light chain 2 (MLC2) signal.
Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study.
Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1.
Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype.
Organelle Stress and Metabolic Derangement in Kidney Disease.
EN1 Regulates Cell Growth and Proliferation in Human Glioma Cells via Hedgehog Signaling.
Lovastatin Inhibits RhoA to Suppress Canonical Wnt/β-Catenin Signaling and Alternative Wnt-YAP/TAZ Signaling in Colon Cancer.
Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance.
The role of SPAG1 in the assembly of axonemal dyneins in human airway epithelia.
Influence of ROCK Pathway Manipulation on the Actin Cytoskeleton Height.
Human Kidney Organoids and Tubuloids as Models of Complex Kidney Disease.
Primary Ciliary Dyskinesia: A Rare and Often Underdiagnosed Disease.
Integrin-β4 regulates the dynamic changes of phenotypic characteristics in association with epithelial-mesenchymal transition (EMT) and RhoA activity in airway epithelial cells during injury and repair.
Cardiomyocyte stromal interaction molecule 1 is a key regulator of Ca2+ -dependent kinase and phosphatase activity in the mouse heart.
The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis of Randomised Studies.
Kidney Injury Causes Accumulation of Renal Sodium That Modulates Renal Lymphatic Dynamics.

Front Med (Lausanne). 2022 ;9 753418

AMPK and Polycystic Kidney Disease Drug Development: An Interesting Off-Target Target.

Michael J Caplan.

  Autosomal Dominant Polycystic Kidney Disease is a genetic disease that causes dramatic perturbations of both renal tissue architecture and of a multitude of cellular signaling pathways. The relationship between the products of the genes whose mutations cause polycystic kidney disease and these signaling pathways remains difficult to determine. It is clear, however, that cellular metabolism is dramatically altered in cells that are affected by polycystic kidney disease mutations. Adenosine monophosphate-stimulated protein kinase is a master regulator of cellular energy use and generation pathways whose activity appears to be perturbed in cells affected by polycystic kidney disease. Furthermore, modulation of this enzyme's activity may constitute a promising approach for the development of new therapeutics for polycystic kidney disease.

Keywords:  Autosomal Dominant Polycystic Kidney Disease; CFTR; adenosine monophosphate-stimulated protein kinase; mTOR; metabolism; metformin

DOI:  https://doi.org/10.3389/fmed.2022.753418
Biochim Biophys Acta Mol Basis Dis. 2022 Feb 09. pii: S0925-4439(22)00021-7. [Epub ahead of print] 166358

Lessons from microRNA biology: Top key cellular drivers of Autosomal Dominant Polycystic Kidney Disease.

Maria Fragiadaki.

   BACKGROUND: Numerous microRNAs (miRs), small RNAs that target several pathways, have been implicated in the development of Autosomal Dominant Polycystic Kidney Disease (ADPKD), which is the most common genetic cause of kidney failure. The hallmark of ADPKD is tissue overgrowth and hyperproliferation, eventually leading to kidney failure.
SCOPE OF THE REVIEW: Many miRs are dysregulated in disease, yet the intracellular pathways regulated by miRs are less well described in ADPKD. Here, I summarise all the differentially expressed miRs in ADPKD and highlight the top miR-regulated cellular driver of disease.
MAJOR CONCLUSIONS: Literature review has identified 53 abnormally expressed miRs in ADPKD. By performing bioinformatics analysis of their target genes I present 10 key intracellular pathways that drive ADPKD progression. The top key drivers are divided into three main areas: (i) hyperproliferation and the role of JAK/STAT and PI3K pathways (ii) DNA damage and (iii) inflammation and NFκB.
GENERAL SIGNIFICANCE: The description of the 10 top cellular drivers of ADPKD, derived by analysis of miR signatures, is of paramount importance in better understanding the key processes resulting in pathophysiological changes that underlie disease.

Keywords:  ADPKD; Chronic kidney disease; DNA damage; NFκB; PI3K; STAT5; microRNAs

DOI:  https://doi.org/10.1016/j.bbadis.2022.166358
J Surg Case Rep. 2022 Feb;2022(2): rjac012

Recurrent thromboses and major vessel compressions in autosomal dominant polycystic kidney disease.

Joel Ern Zher Chan, Zhihong Kuah, Shantanu Bhattacharjya, Santosh Antony Olakkengil.

  A 41-year-old man with autosomal dominant polycystic kidney disease (ADPKD), who had multiple previous unprovoked thrombotic events and without a known coagulopathic disorder, presented with symptomatic extensive thrombus distal to the compression site of the left common iliac vein by a dominant cyst in the left inferior renal pole. This was managed with inferior vena cava filter insertion, left nephrectomy and warfarinization. Later, there was inferior vena cava compression by the right polycystic kidney, leading to elective right nephrectomy. Post-renal transplantation, he had further episodes of partial dialysis access stenosis and extensive thromboses in the left deep and right superficial venous systems of the lower limbs despite absence of extrinsic compression. This represents the first report of recurrent mass effect and thromboembolic events in ADPKD, both before and after nephrectomy and anticoagulation. The potential increased thromboembolic risks among patients with ADPKD warrant further investigation.

Keywords:  autosomal dominant polycystic kidney disease; deep vein thromboses; inferior vena cava; nephrectomy; renal transplantation; venous thromboembolism

DOI:  https://doi.org/10.1093/jscr/rjac012
Cells. 2022 Jan 30. pii: 483. [Epub ahead of print]11(3):

Secreted Neutrophil Gelatinase-Associated Lipocalin Shows Stronger Ability to Inhibit Cyst Enlargement of ADPKD Cells Compared with Nonsecreted Form.

Hsin-Yin Chuang, Wen-Yih Jeng, Ellian Wang, Si-Tse Jiang, Chen-Ming Hsu, Hsiu Mei Hsieh-Li, Yuan-Yow Chiou.

  Polycystic kidney disease (PKD) is one of the most common inherited diseases and is characterized by the development of fluid-filled cysts along multiple segments of the nephron. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD, which is caused by mutations in either PKD1 or PKD2 genes that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. As ADPKD progresses, cysts enlarge and disrupt normal kidney architecture, eventually leading to kidney failure. Our previous study showed that overexpression of exogenous kidney-specific neutrophil gelatinase-associated lipocalin (NGAL) reduced cyst progression and prolonged the lifespan of ADPKD mice (Pkd1L3/L3, 2L3 for short). In this study, we attempted to explore the underlying mechanism of reduced cyst progression in the presence of NGAL using immortalized 2L3 cells. The results of MTT and BrdU incorporation assays showed that recombinant mouse NGAL (mNGAL) protein significantly decreased the viability and proliferation of 2L3 cells. Flow cytometry and western blot analyses showed that mNGAL inhibited activation of the ERK and AKT pathways and induced apoptosis and autophagy in 2L3 cells. In addition, a 3D cell culture platform was established to identify cyst progression in 2L3 cells and showed that mNGAL significantly inhibited cyst enlargement in 2L3 cells. Overexpression of secreted mNGAL (pN + LS) and nonsecreted mNGAL (pN - LS) repressed cell proliferation and cyst enlargement in 2L3 cells and had effects on markers involved in proliferation, apoptosis, and autophagy. However, secreted mNGAL had a more pronounced and consistent effect than that of nonsecreted form. These results reveal that secreted mNGAL has stronger ability to inhibit cyst enlargement of ADPKD cells than that of nonsecreted form. These findings could help to identify strategies for the future clinical treatment of ADPKD.

Keywords:  3D culture; ADPKD; neutrophil gelatinase-associated lipocalin

DOI:  https://doi.org/10.3390/cells11030483
PLoS One. 2022 ;17(2): e0264065

Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use.

Hiroki Mizuno, Akinari Sekine, Tatsuya Suwabe, Daisuke Ikuma, Masayuki Yamanouchi, Eiko Hasegawa, Naoki Sawa, Yoshifumi Ubara, Junichi Hoshino.

Polycystic liver disease (PLD) is a common extrarenal complication of autosomal dominant polycystic kidney disease (ADPKD), which causes compression-related syndrome and ultimately leads to liver dysfunction. Tolvaptan, a V2 receptor antagonist, is widely used to protect kidney function in ADPKD but its effect on PLD remains unknown. An observational cohort study was conducted to evaluate tolvaptan's effect on patients with PLD due to ADPKD. After screening 902 patients, we found the 107 ADPKD patients with PLD who met the criteria of tolvaptan use in Japan. Among them, tolvaptan was prescribed for 62 patients (tolvaptan group), while the other was defined as the non-tolvaptan group. Compared with the non-tolvaptan group, the tolvaptan group had larger height-adjusted total kidney volume (median 994(range 450-4152) mL/m, 513 (405-1928) mL/m, p = 0.01), lower albumin level (mean 3.9±SD 0.4 g/dL, 4.3±0.4g/dL, p<0.01), and higher serum creatinine level (1.2±0.4 mg/dL, 0.9±0.2 mg/dL, p<0.01). Although the median change in annual growth rate of total liver volume (TLV) was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6-18.7) %/year)(p = 0.52), 20 (43.5%) patients in the tolvaptan group experienced a decrease in the growth rate of TLV (responders). A multivariable logistic regression model adjusting for related variables showed that older age (odds ratio 1.15 [95% CI 1.01-1.32]) and a higher growth rate of TLV in the non-tolvaptan period (odds 1.45 95% CI 1.10-1.90) were significantly associated with responders. In conclusion, the change in annual growth rate of TLV in ADPKD patients taking tolvaptan was not statistically different compared with that in ADPKD patients without taking tolvaptan. However, tolvaptan may have the potential to suppress the growth rate of TLV in some PLD patients due to ADPKD, especially in older patients or those that are rapid progressors of PLD. Several limitations were included in this study, therefore well-designed prospective studies were required to confirm the effect of tolvaptan on PLD.

DOI: https://doi.org/10.1371/journal.pone.0264065
Clin Exp Nephrol. 2022 Feb 14.

Initial decline in eGFR to predict tolvaptan response in autosomal-dominant polycystic kidney disease.

Taro Akihisa, Hiroshi Kataoka, Shiho Makabe, Shun Manabe, Rie Yoshida, Yusuke Ushio, Masayo Sato, Ken Tsuchiya, Toshio Mochizuki, Kosaku Nitta.

   BACKGROUND: Tolvaptan, a vasopressin V2 receptor antagonist, is used to treat autosomal-dominant polycystic kidney disease (ADPKD). Although tolvaptan curbs disease progression, a few reports have examined factors related to treatment response. The estimated glomerular filtration rate (eGFR) decreases soon after tolvaptan is initiated. We investigated whether initial eGFR decline affects renal prognosis of patients.
METHODS: This was a single-center, retrospective observational cohort study. Eighty-three patients with ADPKD who initiated tolvaptan were selected. We analyzed the relationship of the initial eGFR change with clinical parameters and analyzed the annual eGFR change in terms of renal prognostic value using univariable and multivariable linear regression analyses.
RESULTS: The initial eGFR change was - 4.6 ± 8.0%/month. The initial eGFR change correlated significantly with the annual eGFR change in multivariable analysis, suggesting that the larger decline in the initial eGFR change, the better the renal prognosis. Furthermore, the change in fractional excretion (FE) of free water (FEH2O) correlated positively with initial eGFR change. FEH2O and urea nitrogen FE (FEUN) increased significantly; however, sodium FE (FENa) level remained unchanged. In approximately half of the patients, FENa unexpectedly decreased.
CONCLUSIONS: The initial eGFR decline might be caused by suppressing glomerular hyperfiltration, due to the pharmacological effect of tolvaptan, and/or by reducing renal plasma flow, due to potential volume depletion. The initial eGFR change reflects the tolvaptan effect, can be easily evaluated in clinical practice, and may be useful as one of the clinical indicator for predicting renal prognosis in patients under tolvaptan.

Keywords:  Autosomal-dominant polycystic kidney disease; Estimated glomerular filtration rate; Initial decline; Renal prognosis; Tolvaptan

DOI:  https://doi.org/10.1007/s10157-022-02192-2
Kidney Int Rep. 2022 Feb;7(2): 270-281

Long-Term Outcomes of Longitudinal Efficacy Study With Tolvaptan in ADPKD.

Eiji Higashihara, Kikuo Nutahara, Masayuki Itoh, Takatsugu Okegawa, Mistuhiro Tambo, Tsuyoshi Yamaguchi, Yu Nakamura, Satoru Taguchi, Shinya Kaname, Kenichi Yokoyama, Tatsuya Yoshioka, Hiroshi Fukuhara.

   Introduction: The effects of long-term and uninterrupted tolvaptan treatment on autosomal dominant polycystic kidney disease (ADPKD) are unclear. Therefore, a more than 3-year continuous treatment study was performed.
Methods: From the Kyorin University cohort, 299 patients were surveyed and 179 patients were indicated for tolvaptan having a total kidney volume (TKV) ≥750 ml, TKV slope ≥5%/yr, and estimated glomerular filtration rate (eGFR) ≥15 ml/min per 1.73 m2. Among 179 patients, 118 patients consented to the study.
Results: Retrospective pretreatment and prospective on-treatment periods had a median of 1.8 and 4.0 years, respectively. During the 5 treatment-years, the log10(TKV) slope/yr decreased from the pretreatment period (P < 0.0001) and the estimated height-adjusted TKV growth rate α (eHTKV-α, %/yr) decreased from baseline (P < 0.0001). The decline in eGFR improved in female patients (P < 0.0001), but not in males (P = 0.6321). Furthermore, during the 5 treatment-years, eGFR remained significantly better in the group with a percent decrease in eHTKV-α from baseline to the first treatment-year ≥ the median (2.94%) than in the group with a decrease <2.94%. The free-water clearance was higher in males than in females irrespective of treatment.
Conclusion: The TKV growth rate decreased in 4 years with tolvaptan in both sexes. The insignificant effects of tolvaptan on the eGFR slope in males were likely due to androgen stimulation of cystogenesis and analytical difficulty of longitudinal changes in nonlinear trajectories of eGFR. The larger decrease in eHTKV-α in the first year was related to a better renal prognosis. The vasopressin-mediated water reabsorption was activated more in females than males irrespective of tolvaptan administration.

Keywords:  autosomal dominant polycystic kidney disease (ADPKD); estimated glomerular filtration rate (eGFR); sex; tolvaptan; total kidney volume (TKV); vasopressin

DOI:  https://doi.org/10.1016/j.ekir.2021.11.034
Exp Mol Med. 2022 Feb 17.

Reduced expression of TAZ inhibits primary cilium formation in renal glomeruli.

Jae Hee Jun, Eun Ji Lee, Minah Park, Je Yeong Ko, Jong Hoon Park.

Renal primary cilia are antenna-like organelles that maintain cellular homeostasis via multiple receptors clustered along their membranes. Recent studies have revealed that YAP/TAZ, key paralogous effectors of the Hippo pathway, are involved in ciliogenesis; however, their independent roles need to be further investigated. Here, we analyzed the renal phenotypes of kidney-specific TAZ knockout mice and observed ciliary defects only in glomeruli where mild cysts were formed. This finding prompted us to verify the role of TAZ specifically in renal tubule ciliary regulation. Therefore, we investigated the effects of TAZ silencing and compared them to those of YAP knockdown using three different types of renal tubular cells. We found that the absence of TAZ prevented proper cilia formation in glomerular cells, whereas it had a negligible effect in collecting duct and proximal tubule cells. IFT and NPHP protein levels were altered because of TAZ deficiency, accompanied by ciliary defects in glomerular cells, and ciliary recovery was identified by regulating some NPHP proteins. Although our study focused on TAZ, ciliogenesis, and other ciliary genes, the results suggest the very distinct roles of YAP and TAZ in kidneys, specifically in terms of ciliary regulation.

DOI: https://doi.org/10.1038/s12276-022-00730-2
Int J Mol Sci. 2022 Feb 03. pii: 1749. [Epub ahead of print]23(3):

PCD Genes-From Patients to Model Organisms and Back to Humans.

Michal Niziolek, Marta Bicka, Anna Osinka, Zuzanna Samsel, Justyna Sekretarska, Martyna Poprzeczko, Rafal Bazan, Hanna Fabczak, Ewa Joachimiak, Dorota Wloga.

  Primary ciliary dyskinesia (PCD) is a hereditary genetic disorder caused by the lack of motile cilia or the assembxly of dysfunctional ones. This rare human disease affects 1 out of 10,000-20,000 individuals and is caused by mutations in at least 50 genes. The past twenty years brought significant progress in the identification of PCD-causative genes and in our understanding of the connections between causative mutations and ciliary defects observed in affected individuals. These scientific advances have been achieved, among others, due to the extensive motile cilia-related research conducted using several model organisms, ranging from protists to mammals. These are unicellular organisms such as the green alga Chlamydomonas, the parasitic protist Trypanosoma, and free-living ciliates, Tetrahymena and Paramecium, the invertebrate Schmidtea, and vertebrates such as zebrafish, Xenopus, and mouse. Establishing such evolutionarily distant experimental models with different levels of cell or body complexity was possible because both basic motile cilia ultrastructure and protein composition are highly conserved throughout evolution. Here, we characterize model organisms commonly used to study PCD-related genes, highlight their pros and cons, and summarize experimental data collected using these models.

Keywords:  Chlamydomonas; Paramecium; Tetrahymena; Trypanosoma; Xenopus; mice; planarian; primary ciliary dyskinesia; zebrafish

DOI:  https://doi.org/10.3390/ijms23031749
Abdom Radiol (NY). 2022 Feb 13.

A MRI-based radiomics nomogram for evaluation of renal function in ADPKD.

Xiaojiao Li, Qingwei Liu, Jingxu Xu, Chencui Huang, Qianqian Hua, Haili Wang, Teng Ma, Zhaoqin Huang.

   OBJECTIVES: This study is aimed to establish a fusion model of radiomics-based nomogram to predict the renal function of autosomal dominant polycystic kidney disease (ADPKD).
METHODS: One hundred patients with ADPKD were randomly divided into training group (n = 69) and test group (n = 31). The radiomics features were extracted from T1-weighted fat suppression images (FS-T1WI) and T2-weighted fat suppression images (FS-T2WI). Decision tree algorithm was employed to build radiomics model to get radiomics signature. Then multivariate logistic regression analysis was used to establish the radiomics nomogram based on independent clinical factors, conventional MR imaging variables and radiomics signature. The receiver operating characteristic (ROC) analysis and Delong test were used to compare the performance of radiomics model and radiomics nomogram model, and the decision curve to evaluate the clinical application value of radiomics nomogram model in the evaluation of renal function in patients with ADPKD.
RESULTS: Fourteen radiomics features were selected to establish radiomics model. Based on FS-T1WI and FS-T2WI sequences, the radiomics model showed good discrimination ability in training group and test group [training group: (AUC) = 0.7542, test group (AUC) = 0.7417]. The performance of radiomics nomogram model was significantly better than that of radiomics model in all data sets [radiomics model (AUC) = 0.7505, radiomics nomogram model (AUC) = 0.8435, p value = 0.005]. The analysis of calibration curve and decision curve showed that radiomics nomogram model had more clinical application value.
CONCLUSION: radiomics analysis of MRI can be used for the preliminary evaluation and prediction of renal function in patients with ADPKD. The radiomics nomogram model shows better prediction effect in renal function evaluation, and can be used as a non-invasive renal function prediction tool to assist clinical decision-making. Trial registration ChiCTR, ChiCTR2100046739. Registered 27 May 2021-retrospectively registered, http://www.ChiCTR.org.cn/showproj.aspx?proj=125955.

Keywords:  Autosomal dominant polycystic key disease; Evaluation of renal function; MRI; radiomics nomogram

DOI:  https://doi.org/10.1007/s00261-022-03433-4
Bioengineered. 2022 Mar;13(3): 5205-5215

Oxycodone relieves permeability damage and apoptosis of oxygen-glucose deprivation/reoxygenation-induced brain microvascular endothelial cells through ras homolog family member A (RhoA)/ Rho-associated coiled-coil containing kinases (ROCK)/ myosin light chain 2 (MLC2) signal.

Fang Shao, Dong Han, Yihui Shen, Wen Bian, Liting Zou, Yiqian Hu, Wei Sun.

  Cerebrovascular disease, an important cause of acute ischemic stroke, has attracted worldwide attention. Oxycodone has been widely used to treat various painful disorders. This study was designed to explore the mechanism of oxycodone in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cell model. For the reliability of the results in the following experiments, the viability was firstly detected using CCK-8. With the application of LDH, TEER and TUNEL assays, the LDH expression, permeability and apoptosis of brain microvascular endothelial cells were detected, respectively. Besides, the mRNA and protein expressions of tight junction proteins and RhoA were measured using RT-qPCR and Western blot. Moreover, RT-qPCR was employed to evaluate the expressions of inflammatory cytokines. Western blot was adopted to measure the levels of RhoA, ROCK, MLC2 and apoptosis-related proteins. The results revealed that oxycodone attenuated permeability damage, inflammatory factor release and apoptosis of OGD/R-induced brain microvascular endothelial cells in a dose-dependent manner. It was also found that oxycodone could reduce the expressions of RhoA, ROCK and MLC2 in brain microvascular endothelial cells induced by OGD/R. More importantly, oxycodone exhibited desirable effects on OGD/R-induced brain microvascular endothelial cells through RhoA/ROCK/MLC2 signal. In conclusion, oxycodone relieved permeability damage and apoptosis of OGD/R-induced brain microvascular endothelial cells through RhoA/ROCK/MLC2 signal, suggesting that oxycodone might be an effective method for the improvement of cerebral ischemia-reperfusion injury.

Keywords:  Oxycodone; RhoA/ROCK/MLC2 signal; oxygen-glucose deprivation/reoxygenation; permeability damage

DOI:  https://doi.org/10.1080/21655979.2022.2037371
Metabolomics. 2022 Feb 18. 18(3): 15

Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study.

Beata Małachowska, Justyna Janikiewicz, Karolina Pietrowska, Krystyna Wyka, Joanna Madzio, Kamila Wypyszczak, Marcin Tkaczyk, Sławomir Chrul, Rafał Zwiech, Anna Hogendorf, Maciej T Małecki, Maciej Borowiec, Adam Krętowski, Wojciech Młynarski, Agnieszka Dobrzyń, Michał Ciborowski, Wojciech Fendler.

   INTRODUCTION: Patients with hepatocyte nuclear factor-1 beta (HNF1B) mutations present a variable phenotype with two main symptoms: maturity onset diabetes of the young (MODY) and polycystic kidney disease (PKD).
OBJECTIVES: Identification of serum metabolites specific for HNF1Bmut and evaluation of their role in disease pathogenesis.
METHODS: We recruited patients with HNF1Bmut (N = 10), HNF1Amut (N = 10), PKD: non-dialyzed and dialyzed (N = 8 and N = 13); and healthy controls (N = 12). Serum fingerprinting was performed by LC-QTOF-MS. Selected metabolite was validated by ELISA (enzyme-linked immunosorbent assay) measurements and then biologically connected with HNF1B by in silico analysis. HepG2 were stimulated with lysophosphatidic acid (LPA) and HNF1B gene was knocked down (kd) by small interfering RNA. Transcriptomic analysis with microarrays and western blot measurements were performed.
RESULTS: Serum levels of six metabolites including: arachidonic acid, hydroxyeicosatetraenoic acid, linoleamide and three LPA (18:1, 18:2 and 20:4), had AUC (the area under the curve) > 0.9 (HNF1Bmut vs comparative groups). The increased level of LPA was confirmed by ELISA measurements. In HepG2HNF1Bkd cells LPA stimulation lead to downregulation of many pathways associated with cell cycle, lipid metabolism, and upregulation of steroid hormone metabolism and Wnt signaling. Also, increased intracellular protein level of autotaxin was detected in the cells. GSK-3alpha/beta protein level and its phosphorylated ratio were differentially affected by LPA stimulation in HNF1Bkd and control cells.
CONCLUSIONS: LPA is elevated in sera of patients with HNF1Bmut. LPA contributes to the pathogenesis of HNF1B-MODY by affecting Wnt/GSK-3 signaling.

Keywords:  Biomarkers; HNF1B; MODY; Maturity-onset diabetes of the young; Metabolomics; Pathogenesis; Polycystic kidney disease

DOI:  https://doi.org/10.1007/s11306-022-01873-z
Elife. 2022 Feb 16. pii: e57593. [Epub ahead of print]11

Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1.

Katarzyna Szymanska, Karsten Boldt, Clare Victoria Logan, Matthew Adams, Philip Alan Robinson, Marius Ueffing, Elton Zeqiraj, Gabrielle Wheway, Colin A Johnson.

  Primary ciliary defects cause a group of developmental conditions known as ciliopathies. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitizes cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. We identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalized, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. We demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1).

Keywords:  cell biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.57593
Int J Mol Sci. 2022 Feb 03. pii: 1753. [Epub ahead of print]23(3):

Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype.

Lawrence E Ostrowski, Weining Yin, Amanda J Smith, Patrick R Sears, Ximena M Bustamante-Marin, Hong Dang, Friedhelm Hildebrandt, Leigh Anne Daniels, Nicole A Capps, Kelli M Sullivan, Margaret W Leigh, Maimoona A Zariwala, Michael R Knowles.

  Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of ODAD1 (CCDC114), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype. We identified a female (now 34 years old) with an unusually mild clinical phenotype who has a homozygous non-canonical splice mutation (c.1502+5G>A) in ODAD1. To investigate the mechanism for the unusual phenotype, we performed molecular and functional studies of cultured nasal epithelial cells. We demonstrate that this splice mutation results in the expression of a truncated protein that is attached to the axoneme, indicating that the mutant protein retains partial function. This allows for the assembly of some ODAs and a significant level of ciliary activity that may result in the atypically mild clinical phenotype. The results also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of disease symptoms.

Keywords:  CCDC114; ODAD1; PCD; cilia; ciliopathy; docking complex; outer dynein arm; primary ciliary dyskinesia

DOI:  https://doi.org/10.3390/ijms23031753
Int J Mol Sci. 2022 Feb 02. pii: 1723. [Epub ahead of print]23(3):

Organelle Stress and Metabolic Derangement in Kidney Disease.

Reiko Inagi.

  Advanced multiomics analysis has revealed novel pathophysiological mechanisms in kidney disease. In particular, proteomic and metabolomic analysis shed light on mitochondrial dysfunction (mitochondrial stress) by glycation in diabetic or age-related kidney disease. Further, metabolic damage often results from organelle stress, such as mitochondrial stress and endoplasmic reticulum (ER) stress, as well as interorganelle communication, or "organelle crosstalk", in various kidney cells. These contribute to progression of the disease phenotype. Aberrant tubular mitochondrial lipid metabolism leads to tubular inflammation and fibrosis. This review article summarizes updated evidence regarding organelle stress, organelle crosstalk, and metabolic derangement in kidney disease.

Keywords:  acute kidney injury; chronic kidney disease; endoplasmic reticulum; lipid metabolism; metabolomics; mitochondria; organelle crosstalk; primary cilia; tubular fibrosis; tubular inflammation

DOI:  https://doi.org/10.3390/ijms23031723
Int J Mol Sci. 2022 Jan 20. pii: 1123. [Epub ahead of print]23(3):

EN1 Regulates Cell Growth and Proliferation in Human Glioma Cells via Hedgehog Signaling.

Jinchun Chang, Chenjia Guo, Jianyu Li, Zhangqian Liang, Yankai Wang, Anliang Yu, Runze Liu, Yuting Guo, Jian Chen, Song Huang.

  Glioblastoma is an aggressive cancer of the nervous system that accounts for the majority of brain cancer-related deaths. Through cross-species transcriptome studies, we found that Engrailed 1 (EN1) is highly expressed in serum-free cultured glioma cells as well as glioma tissues, and increased expression level predicts a worse prognosis. EN1 controls glioma cell proliferation, colony formation, migration, and tumorigenic capacity in vivo. It also influences sensitivity of glioma cells to γ-ray irradiation by regulating intracellular ROS levels. Mechanistically, EN1 influences Hedgehog signaling by regulating the level of Gli1 as well as primary cilia length and the primary cilia transport-related protein TULP3. In conclusion, we demonstrate that EN1 acts as an oncogenic regulator that contributes to glioblastoma pathogenesis and could serve as a diagnostic/prognostic marker and therapeutic target for glioblastoma.

Keywords:  Engrailed; Hedgehog; ROS; glioblastoma; irradiation sensitivity

DOI:  https://doi.org/10.3390/ijms23031123
Cell Transplant. 2022 Jan-Dec;31:31 9636897221075749

Lovastatin Inhibits RhoA to Suppress Canonical Wnt/β-Catenin Signaling and Alternative Wnt-YAP/TAZ Signaling in Colon Cancer.

Yi Xiao, Qin Liu, Nanyin Peng, Yuzhang Li, Danyang Qiu, Tianlun Yang, Richard Kang, Ahsan Usmani, Efosa Amadasu, Cesario V Borlongan, Guolong Yu.

  Statins are first-line drugs used to control patient lipid levels, but there is recent evidence that statin treatment can lower colorectal cancer (CRC) incidence by 50% and prolong CRC patient survival through mechanisms that are poorly understood. In this study, we found that the treatment of APCmin mice by the mevalonate pathway inhibitor lovastatin significantly reduced the number of colonic masses and improved hypersplenism and peripheral anemia. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) analysis of colonic mass tissues showed a potent inhibitory effect in both Wnt/β-catenin signaling and YAP/TAZ signaling in the lovastatin treatment group. The results of our transcriptomic analyses in RKO indicated that lovastatin regulated several proliferation-related signaling pathways. Moreover, lovastatin suppressed important genes and proteins related to the canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ signaling pathways in RKO and SW480 cells, and these effects were rescued by mevalonic acid (MVA), as confirmed through a series of Western blotting, RT-PCR, and reporter assays. Given that statins suppress oncogenic processes primarily through the inhibition of Rho GTPase in the mevalonate pathway, we speculate that lovastatin can inhibit certain Rho GTPases to suppress both canonical Wnt/β-catenin signaling and alternative Wnt-YAP/TAZ signaling. In RKO cells, lovastatin showed similar inhibitory properties as the RhoA inhibitor CCG1423, being able to inhibit β-catenin, TAZ, and p-LATS1 protein activity. Our results revealed that lovastatin inhibited RhoA activity, thereby suppressing the downstream canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ pathways in colon cancer cells. These inhibitory properties suggest the promise of statins as a treatment for CRC. Altogether, the present findings support the potential clinical use of statins in non-cardiovascular contexts and highlight novel targets for anticancer treatments.

Keywords:  RhoA; Wnt-YAP/TAZ signaling; Wnt/β-catenin signaling; colorectal cancer; signaling pathways; statins; stem cells

DOI:  https://doi.org/10.1177/09636897221075749
Int J Mol Sci. 2022 Feb 03. pii: 1733. [Epub ahead of print]23(3):

Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance.

Ngoc Minh Nguyen, Jungsook Cho.

  Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.

Keywords:  basal cell carcinoma; drug resistance; hedgehog inhibitor; hedgehog signaling; smoothened inhibitor; targeted cancer therapy

DOI:  https://doi.org/10.3390/ijms23031733
J Cell Sci. 2022 Feb 18. pii: jcs.259512. [Epub ahead of print]

The role of SPAG1 in the assembly of axonemal dyneins in human airway epithelia.

Amanda J Smith, Ximena M Bustamante-Marin, Weining Yin, Patrick R Sears, Laura E Herring, Nedyalka N Dicheva, Francesc López-Giráldez, Shrikant Mane, Robert Tarran, Margaret W Leigh, Michael R Knowles, Maimoona A Zariwala, Lawrence E Ostrowski.

  Mutations in SPAG1, a dynein axonemal assembly factor (DNAAF) that facilitates the assembly of dynein arms in the cytoplasm before their transport into the cilium, result in primary ciliary dyskinesia (PCD), a genetically heterogenous disorder characterized by chronic oto-sino-pulmonary disease, infertility, and laterality defects. To further elucidate SPAG1's role in dynein assembly, we examined its expression, interactions, and ciliary defects in control and PCD human airway epithelia. Immunoprecipitations showed that SPAG1 interacts with multiple DNAAFs, dynein chains, and canonical components of the R2TP complex. Dynein heavy chains (DHC) protein levels and their interaction with dynein intermediate chains (DIC) were reduced in SPAG1 mutants. We also identified a previously uncharacterized 60 kDa SPAG1 isoform, through examination of PCD subjects with an atypical ultrastructural defect for SPAG1 variants, that can partially compensate for the absence of full-length SPAG1 to assemble a reduced number of outer dynein arms. In summary, our data show that SPAG1 is necessary for axonemal dynein arm assembly by scaffolding R2TP-like complexes composed of several DNAAFs that facilitate the folding and/or binding of the DHC to the DIC complex.

Keywords:  Dynein Arm Assembly; Motile Cilia; Primary Ciliary Dyskinesia; R2TP Complex; SPAG1

DOI:  https://doi.org/10.1242/jcs.259512
Cells. 2022 Jan 26. pii: 430. [Epub ahead of print]11(3):

Influence of ROCK Pathway Manipulation on the Actin Cytoskeleton Height.

Carolin Grandy, Fabian Port, Jonas Pfeil, Kay-Eberhard Gottschalk.

  The actin cytoskeleton with its dynamic properties serves as the driving force for the movement and division of cells and gives the cell shape and structure. Disorders in the actin cytoskeleton occur in many diseases. Deeper understanding of its regulation is essential in order to better understand these biochemical processes. In our study, we use metal-induced energy transfer (MIET) as a tool to quantitatively examine the rarely considered third dimension of the actin cytoskeleton with nanometer accuracy. In particular, we investigate the influence of different drugs acting on the ROCK pathway on the three-dimensional actin organization. We find that cells treated with inhibitors have a lower actin height to the substrate while treatment with a stimulator for the ROCK pathway increases the actin height to the substrate, while the height of the membrane remains unchanged. This reveals the precise tuning of adhesion and cytoskeleton tension, which leads to a rich three-dimensional structural behaviour of the actin cytoskeleton. This finetuning is differentially affected by either inhibition or stimulation. The high axial resolution shows the importance of the precise finetuning of the actin cytoskeleton and the disturbed regulation of the ROCK pathway has a significant impact on the actin behavior in the z dimension.

Keywords:  ROCK pathway; actin cytoskeleton; metal-induced energy transfer; z-dimension

DOI:  https://doi.org/10.3390/cells11030430
Am J Pathol. 2022 Feb 15. pii: S0002-9440(22)00046-3. [Epub ahead of print]

Human Kidney Organoids and Tubuloids as Models of Complex Kidney Disease.

Ana B Nunez-Nescolarde, David J Nikolic-Paterson, Alexander N Combes.

Kidney organoids derived from pluripotent stem cells and epithelial organoids derived from adult tissue (tubuloids) have been used to study various kidney disorders with a strong genetic component such as polycystic kidney disease, Wilms tumor and congenital nephrotic syndrome. However, complex disorders without clear genetic associations, such as acute kidney injury and many forms of chronic kidney disease, are only just beginning to be investigated using these in vitro approaches. While organoids are a reductionist model, they contain clinically relevant cell populations that may help to elucidate human-specific pathogenic mechanisms. Thus, organoids may complement animal disease models to accelerate the translation of laboratory proof-of-concept research into clinical practice. This review discusses whether kidney organoids and tubuloids are suitable models for the study of complex human kidney disease and highlights their advantages and limitations compared to monolayer cell culture and animal models.

DOI: https://doi.org/10.1016/j.ajpath.2022.01.009
Pediatr Ann. 2022 Feb;51(2): e82-e85

Primary Ciliary Dyskinesia: A Rare and Often Underdiagnosed Disease.

Avani Shah, Theresa A Laguna.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease with clinical features of ear, sinus, and pulmonary infections that overlap with common respiratory illnesses of childhood. It is a progressive disorder that has significant influence on quality of life, lung function, and survival. Given the considerable overlap of symptoms between common illnesses and PCD, a high index of suspicion by primary care providers is needed to consider the diagnosis. There is not a single "gold standard" diagnostic test for PCD and multiple diagnostic methods coupled with specialized expertise is often needed to make the diagnosis. Patients with PCD also have comorbidities requiring a multidisciplinary approach for optimal clinical management. It is important for primary care physicians to recognize the PCD clinical phenotype and have a diagnostic framework for these patients. [Pediatr Ann. 2022;51(2):e82-e85.].

DOI: https://doi.org/10.3928/19382359-20220119-01
Int J Biol Sci. 2022 ;18(3): 1254-1270

Integrin-β4 regulates the dynamic changes of phenotypic characteristics in association with epithelial-mesenchymal transition (EMT) and RhoA activity in airway epithelial cells during injury and repair.

Mei-Ling Tan, Wen-Jie Huang, Yue Wang, Lei Liu, Yan Pan, Jing-Jing Li, Jiang Zhang, Mingxing Ouyang, Xiang-Ping Qu, Hui-Jun Liu, Chi Liu, Dan Zeng, Xiao-Qun Qin, Linhong Deng, Yang Xiang.

  Background: In airway disease such as asthma a hyperactive cellular event of epithelial-mesenchymal transition (EMT) is considered as the mechanism of pathological airway tissue remodeling after injury to the airway epithelium. And the initiation of EMT in the airways depends on the epithelial disruption involving dissolution and/or destabilization of the adhesive structures between the cells and ECM. Previously, we have shown that integrin-β4, an epithelial adhesion molecule in bronchial epithelium is an important regulator of cell proliferation and wound repair in human airway epithelial cells. Therefore, in this study we aimed to investigate whether integrin-β4 also regulates EMT phenotypes during injury and repair in airway epithelial cells of both wild type/integrin-β4-/- mice in vivo and cultured cells treated with integrin-β4/nonsense siRNA in vitro. Methods: We induced injury to the airway epithelial cells by either repeated exposure to ozone and mechanical scratch wound, and subsequently examined the EMT-related phenotypic features in the airway epithelial cells including biomarkers expression, adhesion and cytoskeleton reorganization and cell stiffness. Results: The results show that in response to injury (ozone exposure/scratch wound) and subsequent spontaneous repair (ozone withdrawal/wound healing) both in vivo and in vitro, the airway epithelial cells underwent dynamic changes in the epithelial and mesenchymal biomarkers expression, adhesion and cytoskeleton structures as well as cell stiffness, all together exhibiting enhanced EMT phenotypic features after injury and reversal of the injury-induced effects during repair. Importantly, these injury/repair-associated EMT phenotypic changes in airway epithelial cells appeared to be dependent on integrin-β4 expression. More specifically, when integrin-β4 was deficient in mice (integrin-β4-/-) the repair of ozone-injured airway epithelium was impaired and the recovery of ozone-enhanced EMT biomarkers expression in the airway epithelium was delayed. Similarly, in the scratch wounded airway epithelial cells with integrin-β4 knockdown, the cells were impaired in all aspects related to EMT during wound and repair including cell proliferation, wound closure rate, adhesion and cytoskeleton protein expression (vinculin and vimentin), mesenchymal-like F-actin reorganization, cell stiffness and RhoA activation. Conclusion: Taken together, these results suggested that integrin-β4 may be essential in regulating the effects of injury and repair on EMT in airway epithelial cells via influencing both the cell adhesion to ECM and cells' physical phenotypes through RhoA signaling pathway.

Keywords:  Airway epithelium; EMT; cell stiffness; integrin-β4; wound repair

DOI:  https://doi.org/10.7150/ijbs.65174
Physiol Rep. 2022 Feb;10(4): e15177

Cardiomyocyte stromal interaction molecule 1 is a key regulator of Ca2+ -dependent kinase and phosphatase activity in the mouse heart.

Helen E Collins, Joshua C Anderson, Adam R Wende, John C Chatham.

  Stromal interaction molecule 1 (STIM1) is a major regulator of store-operated calcium entry in non-excitable cells. Recent studies have suggested that STIM1 plays a role in pathological hypertrophy; however, the physiological role of STIM1 in the heart is not well understood. We have shown that mice with a cardiomyocyte deletion of STIM1 (cr STIM1-/- ) develop ER stress, mitochondrial, and metabolic abnormalities, and dilated cardiomyopathy. However, the specific signaling pathways and kinases regulated by STIM1 are largely unknown. Therefore, we used a discovery-based kinomics approach to identify kinases differentially regulated by STIM1. Twelve-week male control and cr STIM1-/- mice were injected with saline or phenylephrine (PE, 15 mg/kg, s.c, 15 min), and hearts obtained for analysis of the Serine/threonine kinome. Primary analysis was performed using BioNavigator 6.0 (PamGene), using scoring from the Kinexus PhosphoNET database and GeneGo network modeling, and confirmed using standard immunoblotting. Kinomics revealed significantly lower PKG and protein kinase C (PKC) signaling in the hearts of the cr STIM1-/- in comparison to control hearts, confirmed by immunoblotting for the calcium-dependent PKC isoform PKCα and its downstream target MARCKS. Similar reductions in cr STIM1-/- hearts were found for the kinases: MEK1/2, AMPK, and PDPK1, and in the activity of the Ca2+ -dependent phosphatase, calcineurin. Electrocardiogram analysis also revealed that cr STIM1-/- mice have significantly lower HR and prolonged QT interval. In conclusion, we have shown several calcium-dependent kinases and phosphatases are regulated by STIM1 in the adult mouse heart. This has important implications in understanding how STIM1 contributes to the regulation of cardiac physiology and pathophysiology.

Keywords:  calcium-dependent; cardiomyocytes; kinases; protein kinase C (PKC); protein kinase G (PKG); store-operated calcium entry (SOCE); stromal interaction molecule 1 (STIM1)

DOI:  https://doi.org/10.14814/phy2.15177
J Clin Med. 2022 Jan 31. pii: 768. [Epub ahead of print]11(3):

The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis of Randomised Studies.

Alexandros Hadjivasilis, Panayiotis Kouis, Andreas Kousios, Andrie Panayiotou.

   AIM: Fibrates have proven efficacy in cardiovascular risk reduction and are commonly used, in addition to statins, to control hypertriglyceridaemia. Their use is often limited due to reduction in glomerular filtration rate at treatment initiation. However, recent studies suggest benign changes in kidney function and improvement of proteinuria, an established early marker of microvascular disease and kidney disease progression. We summarize the evidence from existing trials and provide a summary of effects of fibrates, alone or in combination, on kidney disease progression and proteinuria.
METHODS AND RESULTS: Systematic review and meta-analysis of randomized, controlled trials (PROSPERO CRD42020187764). Out of 12,243 potentially eligible studies, 29 were included in qualitative and quantitative analysis, with a total of 20,176 patients. Mean creatinine increased by 1.05 (95% CI (0.63 to 1.46)) units in patients receiving fibrates vs. comparator, and this was similar in all other subgroups. eGFR showed a bigger decrease in the fibrates arm (SMD -1.99; 95% CI (-3.49 to -0.48)) when all studies were pooled together. Notably, short-term serum creatinine and eGFR changes remained constant in the long-term. Pooled estimates show that fibrates improve albuminuria progression, RR 0.86; 95% CI (0.76 to 0.98); albuminuria regression, RR 1.19; 95% CI (1.08 to 1.310).
CONCLUSIONS: Fibrates improve albuminuria in patients with and without diabetes when used to treat hyperlipidaemia. The modest creatinine increase should not be a limiting factor for fibrate initiation in people with preserved renal function or mild CKD. The long-term effects on kidney disease progression warrant further study.

Keywords:  cardivacular disease; fibrates; proteinuria; renal function

DOI:  https://doi.org/10.3390/jcm11030768
Int J Mol Sci. 2022 Jan 27. pii: 1428. [Epub ahead of print]23(3):

Kidney Injury Causes Accumulation of Renal Sodium That Modulates Renal Lymphatic Dynamics.

Jing Liu, Elaine L Shelton, Rachelle Crescenzi, Daniel C Colvin, Annet Kirabo, Jianyong Zhong, Eric J Delpire, Hai-Chun Yang, Valentina Kon.

  Lymphatic vessels are highly responsive to changes in the interstitial environment. Previously, we showed renal lymphatics express the Na-K-2Cl cotransporter. Since interstitial sodium retention is a hallmark of proteinuric injury, we examined whether renal sodium affects NKCC1 expression and the dynamic pumping function of renal lymphatic vessels. Puromycin aminonucleoside (PAN)-injected rats served as a model of proteinuric kidney injury. Sodium 23Na/1H-MRI was used to measure renal sodium and water content in live animals. Renal lymph, which reflects the interstitial composition, was collected, and the sodium analyzed. The contractile dynamics of isolated renal lymphatic vessels were studied in a perfusion chamber. Cultured lymphatic endothelial cells (LECs) were used to assess direct sodium effects on NKCC1. MRI showed elevation in renal sodium and water in PAN. In addition, renal lymph contained higher sodium, although the plasma sodium showed no difference between PAN and controls. High sodium decreased contractility of renal collecting lymphatic vessels. In LECs, high sodium reduced phosphorylated NKCC1 and SPAK, an upstream activating kinase of NKCC1, and eNOS, a downstream effector of lymphatic contractility. The NKCC1 inhibitor furosemide showed a weaker effect on ejection fraction in isolated renal lymphatics of PAN vs controls. High sodium within the renal interstitium following proteinuric injury is associated with impaired renal lymphatic pumping that may, in part, involve the SPAK-NKCC1-eNOS pathway, which may contribute to sodium retention and reduce lymphatic responsiveness to furosemide. We propose that this lymphatic vessel dysfunction is a novel mechanism of impaired interstitial clearance and edema in proteinuric kidney disease.

Keywords:  NKCC1 transporter; kidney; lymphatics; sodium

DOI:  https://doi.org/10.3390/ijms23031428