bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–11–06
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne



  1. Arch Gynecol Obstet. 2022 Oct 31.
       PURPOSE: Report on the diagnosis of prenatally detected fetal kidneys with bilateral polycystic appearance in a single center between 1999 and 2020 with special focus on renal morphology and biometry, amniotic fluid and extrarenal findings and proposal for an diagnostic algorithm.
    METHODS: Retrospective observational study including pregnancies with prenatally detected kidneys with bilateral polycystic appearance (n = 98). Cases and outcomes were compared according to prenatal findings with special focus on renal morphology, amount of amniotic fluid, and presence of extrarenal abnormalities.
    RESULTS: Most frequent diagnoses were autosomal recessive polycystic kidney disease (ARPKD, 53.1%), Meckel-Gruber syndrome (MKS, 17.3%) and autosomal dominant polycystic kidney disease (ADPKD, 8.2%). Other diagnoses included: Joubert-, Jeune-, McKusick-Kaufman- and Bardet-Biedl syndrome, overgrowth syndromes, Mainzer-Saldino syndrome and renal tubular dysgenesis. Renal abnormalities most frequently observed were hyperechogenic parenchyma, kidney enlargement, changes of corticomedullary differentiation and cystic changes of various degree. Oligo- and anhydramnios were mainly seen in ARPKD, RTD and second-trimester MKS. Extrarenal findings included skeletal (35.7%) and cardiac (34.7%) abnormalities as well as abnormalities of the central nervous system (27.6%).
    CONCLUSION: Gestational age at manifestation, kidney size, visibility of cysts, echogenicity, amniotic fluid volume, and the presence of associated extrarenal malformations allow to differentiate between the most frequent underlying diseases presenting with bilateral polycystic kidneys on prenatal ultrasound by following a diagnostic algorithm.
    Keywords:  ADPKD; ARPKD; Ciliopathies; Corticomedullary differentiation; Hyperechogenic kidneys
    DOI:  https://doi.org/10.1007/s00404-022-06814-8
  2. Mol Biol Cell. 2022 Nov 02. mbcE22080373
      The serine-threonine kinase Tau Tubulin Kinase 2 (TTBK2) is a key regulator of the assembly of primary cilia, which are vital signaling organelles. TTBK2 is also implicated in the stability of the assembled cilium, through mechanisms that remain to be defined. Here, we use mouse embryonic fibroblasts (MEFs) derived from Ttbk2fl/fl; UBC-CreERT+ embryos (hereafter Ttbk2cmut) to dissect the role of TTBK2 in cilium stability. This system depletes TTBK2 levels after cilia formation, allowing us to assess the molecular changes to the assembled cilium over time. As a consequence of Ttbk2 deletion, the ciliary axoneme is destabilized and primary cilia are lost within 48-72 hours following recombination. Axoneme destabilization involves an increased frequency of cilia breaks and a reduction in axonemal microtubule modifications. Cilia loss was delayed by using inhibitors that affect actin-based trafficking. At the same time, we find that TTBK2 is required to regulate the composition of the centriolar satellites and to maintain the basal body pools of intraflagellar transport (IFT) proteins. Altogether, our results reveal parallel pathways by which TTBK2 maintains cilium stability. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E22-08-0373
  3. Nat Commun. 2022 Oct 30. 13(1): 6497
      Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41467-022-34255-z
  4. J Med Ultrason (2001). 2022 Nov 05.
       PURPOSE: Tolvaptan is the first approved treatment for autosomal dominant polycystic kidney disease (ADPKD) that targets a mechanism directly contributing to the development and growth of renal cysts. We investigated the ability of ultrasonography to predict total kidney volume (TKV) of 750 mL or more, which is an indication for tolvaptan therapy in patients with ADPKD.
    METHODS: A total of 46 patients with ADPKD were evaluated. The most statistically appropriate measurement based on ultrasonography for predicting TKV determined by computed tomography (CT) was assessed.
    RESULTS: TKV determined by CT was 796.8 (508.8-1,560.3) mL. The median length, anteroposterior distance, and mediolateral distance determined using ultrasonography were 15.7 cm, 7.6 cm, and 7.6 cm in the left kidney, and 13.4 cm, 6.9 cm, and 7.2 cm in the right kidney, respectively. Multivariate regression analysis showed that total kidney length (left and right) [variance inflation factor (VIF), 9.349] and total mediolateral distance (left and right) (VIF, 3.988) were independently associated with TKV. The correlation (r) between the logarithm of TKV determined by CT and total mediolateral distance determined using ultrasonography was 0.915 (p < 0.001). The linear regression equation was log (total kidney volume) = 1.833 + 0.075 × total mediolateral distance (left and right) based on ultrasonography. The area under the receiver operating characteristic curve for total mediolateral distance determined using ultrasonography to predict TKV of 750 mL or more was 0.989. Using the total mediolateral distance cut-off value of 14.2 cm, the sensitivity and specificity were 96.0% and 100.0%, respectively.
    CONCLUSION: Total mediolateral distance determined using ultrasonography can predict TKV in patients with ADPKD.
    Keywords:  Autosomal dominant polycystic kidney disease; Tolvaptan; Total kidney volume; Ultrasonography
    DOI:  https://doi.org/10.1007/s10396-022-01261-z
  5. Respir Res. 2022 Oct 29. 23(1): 292
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder, mainly characterized by the development of renal cysts, as well as various extrarenal manifestations. Previous studies have shown that ADPKD is related to bronchiectasis, while its pathogenic mechanism is unclear. In previous studies, we have generated the PKD1+/- pigs to simulate the progression of cyst formation and physiological alterations similar to those seen in ADPKD patients.
    METHODS: Phenotypic changes to airway epithelial cell and mesenchymal cell in PKD1+/- pigs were assessed by histological analysis. The molecular mechanisms driving these processes were investigated by using PKD1+/- pig lungs, human mesenchymal cells, and generating PKD1 deficient human epithelial cells.
    RESULTS: We identified bronchiectasis in PKD1+/- pigs, which is consistent with the clinical symptoms in ADPKD patients. The deficiency of PKD1 suppressed E-cadherin expression in the airway epithelial barrier, which aggravated invasion and leaded to a perpetuated inflammatory response. During this process, extracellular matrix (ECM) components were altered, which contributed to airway smooth muscle cell phenotype switch from a contractile phenotype to a proliferative phenotype. The effects on smooth muscle cells resulted in airway remodeling and establishment of bronchiectasis.
    CONCLUSION: To our knowledge, the PKD1+/- pig provides the first model recapitulating the pathogenesis of bronchiectasis in ADPKD. The role of PKD1 in airway epithelial suggests a potential target for development of new strategies for the diagnosis and treatment of bronchiectasis.
    Keywords:  ADPKD; Bronchiectasis; E-cadherin; PKD1; Pig
    DOI:  https://doi.org/10.1186/s12931-022-02214-3
  6. Hum Mol Genet. 2022 Nov 02. pii: ddac273. [Epub ahead of print]
      Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes and is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1 (MCP-1). Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.
    DOI:  https://doi.org/10.1093/hmg/ddac273
  7. Blood Purif. 2022 Nov 01. 1-9
       INTRODUCTION: Among end-stage kidney disease (ESKD) patients on dialysis with autosomal dominant polycystic kidney disease (ADPKD), relatively little is known about the epidemiology and risk factors for 30-day readmissions in the USA. Therefore, we evaluated the 30-day unplanned readmission rates and predictors and inpatient care costs among ESKD patients with and without ADPKD using a nationally representative, all-payer database.
    METHODS: We utilized the Nationwide Readmissions Database from 2013 to 2018 to identify patients admitted for ESKD on dialysis with and without ADPKD using ICD-9 and ICD-10 codes. The primary outcome was a 30-day, unplanned readmission rate. Secondary outcomes were readmission reasons and timing, mortality, cost of hospitalization and rehospitalization, and adjusted predictors of readmissions. We used χ2 tests, t tests, and Wilcoxon rank-sum tests for descriptive analyses and survey logistic regression to calculate adjusted odds ratios and 95% confidence intervals for associations with readmissions adjusting for confounders.
    RESULTS: From 2013 to 2018, in a cohort of 1,404,144 hospitalizations with ESKD on dialysis as the primary and secondary diagnosis on index admission, there were 8,213 (0.58%) patients with ADPKD and 1,395,932 patients without ADPKD. Those who had ADPKD during index admissions had fewer 30 days readmissions (18.8 vs. 23.8%, p < 0.0001). The cost of hospitalizations and readmissions in ESKD on-dialysis patients with ADPKD was higher than non-ADPKD patients. Compared to ESKD patients without ADPKD who were readmitted, readmitted ADPKD patients were more likely to be younger with a lower Elixhauser Comorbidity Index (ECI) score; have received kidney transplant, lower source of income, elective index admissions, private insurance; and be discharged routinely, admitted in hospitals with larger bed size, in teaching hospitals, and less likely to get admitted through the emergency department. Younger age (<75 years), higher ECI score, longer length of stay, Medicare and Medicaid insurance, self-pay, discharge to a short-term hospital, specialized care, home health care, and against medical advice were associated with significantly increased odds of readmission. ADPKD patients were 31% less likely to get readmitted and 43% less likely to die during readmissions.
    DISCUSSION/CONCLUSION: Nationwide, ESKD on-dialysis patients with ADPKD were less likely to have 30-day readmission than patients without ADPKD. Inpatient mortality during readmissions in patients admitted with ESKD on dialysis was lower with ADPKD as compared to those without ADPKD at the cost of higher health care expenses.
    Keywords:  Autosomal dominant polycystic kidney disease; End-stage kidney disease on dialysis; Epidemiology; Nationwide Readmissions Database; Readmission rates
    DOI:  https://doi.org/10.1159/000526923
  8. Int J Tryptophan Res. 2022 ;15 11786469221126063
      Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls (P ⩽ .05). LPK kidneys also showed an age effect (P ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls (P ⩽ .05). Plasma XA and 3-HK also showed an age effect (P ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect (P ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD.
    Keywords:  Kynurenine pathway; chronic kidney disease; nephronophthisis; polycystic kidney disease; tryptophan
    DOI:  https://doi.org/10.1177/11786469221126063
  9. J Ren Nutr. 2022 Oct 30. pii: S1051-2276(22)00196-0. [Epub ahead of print]
       OBJECTIVE: To describe the quality and health literacy demand of publicly available diet related videos on YouTube for people with Polycystic Kidney Disease (PKD).
    DESIGN AND METHODS: This desk-based content analysed involved a comprehensive search of YouTube using key words relating to the dietary management of people with PKD. The health literacy demand was evaluated using the Patient Education Material Assessment Tool (PEMAT) for audio-visual materials. A PEMAT score of >70% is indicative of videos that are understandable and actionable.
    RESULTS: A total of 15 videos were evaluated (median 1.28 minutes duration (range: 55 seconds to 81 minutes). The majority were produced by reputable sources (such as a PKD related charity (n= 12) or Nephrologist (n= 2). The quality of the videos was high with the majority (14/15) providing evidence-based advice. The understandability and actionability of the videos were considered low (median PEMAT score 67% (IQR: 51.4-81.7) and 66.83 % (IQR: 50-67) respectively.
    CONCLUSION: There has been a small increase in the number of diet related videos for people with PKD in the past five years. The majority provide evidence-based information, which is also a substantial improvement since the last analysis in 2015. Unfortunately, the health literacy demand of these resources remains suboptimal, and future work should be directed to improving the understandability and actionability of videos.
    Keywords:  PKD; YouTube; content analysis; diet; evidence based; health literacy; nutrition
    DOI:  https://doi.org/10.1053/j.jrn.2022.10.006
  10. Nephrol Dial Transplant. 2022 Oct 29. pii: gfac298. [Epub ahead of print]
       BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by a unique bone and mineral phenotype. The impact of Tolvaptan treatment on mineral metabolism and bone mineral density is unknown.
    METHODS: We conducted an analysis in the Bern ADPKD registry, a prospective observational cohort study. Mineral metabolism parameters were measured at baseline and every 12 months thereafter. Bone mineral density was determined by dual-energy X-ray absorptiometry at baseline and after 3 years. Multivariable mixed-effects regression models were applied to assess changes in mineral metabolism parameters and bone mineral density associated with Tolvaptan treatment.
    RESULTS: A total of 189 participants (122 without and 67 with subsequent Tolvaptan treatment) were included in the analysis. During follow-up, Tolvaptan treatment was associated with increased bone mineral density at the femoral neck (β 0.092; 95% CI 0.001, 0.183; p = 0.047). In addition, Tolvaptan treatment was associated with higher plasma magnesium (β 0.019; 95% CI 0.001, 0.037; p = 0.037), bicarbonate (β 0.972; 95% CI 0.242, 1.702; p = 0.009) and urine pH (β 0.214; 95% CI 0.056, 0.372; p = 0.008), and lower parathyroid hormone (β -0.191; 95% CI -0.328, -0.053; p = 0.006), 1,25-(OH)2-Vitamin D3 (β -0.126; 95% CI -0.235, -0.164; p = 0.024) and fractional urinary magnesium excretion (β -0.473; 95% CI -0.622, -0.324; p < 0.001).
    CONCLUSIONS: Chronic Tolvaptan treatment is associated with increased femoral bone mineral density and significant changes in both mineral metabolism and acid-base parameters in ADPKD patients.
    Keywords:  ADPKD; Tolvaptan; bone mineral density; mineral metabolism
    DOI:  https://doi.org/10.1093/ndt/gfac298
  11. Insect Sci. 2022 Nov 03.
      Cilia are microtubule-based, hair-like organelles involved in sensory function or motility, playing critical roles in many physiological processes such as reproduction, organ development, and sensory perception. In insects, cilia are restricted to certain sensory neurons and sperms, being important for chemical and mechanical sensing, and fertility. Although great progress has been made regarding the mechanism of cilia assembly, the formation of insect cilia remains poorly understand, even in the insect model organism Drosophila. Intraflagellar transport (IFT) is a cilia-specific complex that traffics protein cargos bidirectionally along the ciliary axoneme and is essential for most cilia. Here we investigated the role of IFT52, a core component of IFT-B, in cilia/flagellar formation of Drosophila. We show that Drosophila IFT52 is distributed along the sensory neuronal cilia, and is essential for sensory cilia formation. Deletion of Ift52 results in severe defects in cilia-related sensory behaviors. It should be noted that IFT52 is not detected in spermatocyte cilia or sperm flagella of Drosophila. Accordingly, ift52 mutants can produce sperms with normal motility, supporting a dispensable role of IFT in Drosophila sperm flagella formation. Altogether, IFT52 is a conserved protein essential for sensory cilia formation and sensory neuronal function in insects. This article is protected by copyright. All rights reserved.
    Keywords:  Drosophila; IFT52; sensory cilia; sperm flagella
    DOI:  https://doi.org/10.1111/1744-7917.13140
  12. Clin Nephrol. 2022 Nov 04.
      We report two cases of HNF1-β gene variation diagnosed in infancy, in whom fetal ultrasonography revealed enhanced echogenicity and multiple cysts in the renal parenchyma of both patients. They were initially diagnosed as autosomal recessive polycystic kidney disease. Gene testing showed a variation of HNF1-β gene, one showed chromosome 17q12 deletion including HNF1-β, the other was a de novo nonsense mutation in the HNF1-β gene. The two children showed different renal function states. Extrarenal phenotypes also vary widely according to HNF1-β gene variation including early-onset diabetes, autism spectrum, cognitive disorders, liver function abnormalities, and genital malformations, etc. We emphasize the importance of performing gene detection in order to make an accurate diagnosis, especially in those with fetal hyperechogenic kidneys, and so as to carry out reasonable multidisciplinary management. Early intervention for diabetes and neurodevelopmental disorders are especially important.
    DOI:  https://doi.org/10.5414/CN110895
  13. J Clin Invest. 2022 Nov 03. pii: e153943. [Epub ahead of print]
      The Hippo pathway nuclear effector Yes-associated protein 1 (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1) driven by ERK1/2 and PI3K/AKT cascades induced endoplasmic reticulum (ER) proteotoxic stress. To reduce it by reprogramming translation, the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF-S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α-phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress-ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan, impeded these processes. Restoring ER homeostasis, and/or interfering with the SKP2-YAP interaction represent novel potential therapeutic avenues for stemming the progression of renal cystogenesis.
    Keywords:  Chronic kidney disease; Nephrology
    DOI:  https://doi.org/10.1172/JCI153943
  14. J Cell Biol. 2022 Dec 05. pii: e202203081. [Epub ahead of print]221(12):
      The centriole is the microtubule-based backbone that ensures integrity, function, and cell cycle-dependent duplication of centrosomes. Mostly unclear mechanisms control structural integrity of centrioles. Here, we show that the centrosome protein CEP350 functions as scaffold that coordinates distal-end properties of centrioles such as length, stability, and formation of distal and subdistal appendages. CEP350 fulfills these diverse functions by ensuring centriolar localization of WDR90, recruiting the proteins CEP78 and OFD1 to the distal end of centrioles and promoting the assembly of subdistal appendages that have a role in removing the daughter-specific protein Centrobin. The CEP350-FOP complex in association with CEP78 or OFD1 controls centriole microtubule length. Centrobin safeguards centriole distal end stability, especially in the compromised CEP350-/- cells, while the CEP350-FOP-WDR90 axis secures centriole integrity. This study identifies CEP350 as a guardian of the distal-end region of centrioles without having an impact on the proximal PCM part.
    DOI:  https://doi.org/10.1083/jcb.202203081