bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–02–12
nineteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. An Objective Pain Assessment for Autosomal Dominant Polycystic Kidney Disease (ADPKD): A Patient's Perspective.
  2. A Step Ahead toward Measuring Pain in Autosomal Dominant Polycystic Kidney Disease (ADPKD).
  3. Ciliary mechanosensation - roles of polycystins and mastigonemes.
  4. Polycystin Channel Complexes.
  5. Concurrent Targeting of Vasopressin Receptor 2 and Somatostatin Receptors in Autosomal Dominant Polycystic Kidney Disease: A Promising Approach for Autosomal Dominant Polycystic Kidney Disease Treatment?
  6. Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model.
  7. Intraductal Papillary Mucinous Neoplasm of the Pancreas Associated with Polycystic Liver and Kidney Disease.
  8. Blocker displacement amplification-based genetic diagnosis for autosomal dominant polycystic kidney disease and the clinical outcomes of preimplantation genetic testing.
  9. The Rab GTPase-binding protein EHBP1L1 and its interactors CD2AP/CIN85 negatively regulate the length of primary cilia via actin remodeling.
  10. The genetic landscape of autosomal dominant polycystic kidney disease in Kuwait.
  11. Development of a Patient-Reported Outcomes Tool to Assess Pain and Discomfort in Autosomal Dominant Polycystic Kidney Disease.
  12. Acute renal intracystic hemorrhage in patients with autosomal dominant polycystic kidney disease.
  13. Primary cilia, AKAPs and constitutive activity at the orphan G protein-coupled receptor GPR161: a tale about a tail.
  14. Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial.
  15. Microvascular perfusion, perfused boundary region and glycocalyx shedding in patients with autosomal dominant polycystic kidney disease: results from the GlycoScore III study.
  16. Lithium-induced ciliary lengthening sparks Arp2/3 complex-dependent endocytosis.
  17. Initial ciliary assembly in Chlamydomonas requires Arp2/3 complex-dependent endocytosis.
  18. Rho-kinase inhibitor restores glomerular fatty acid metabolism in diabetic kidney disease.
  19. Shorter Cilia Length and Aberrant Ciliated Marker DNAI1 in Allergic Rhinitis.
  1. Clin J Am Soc Nephrol. 2023 Feb 01. 18(2): 147-148
    An Objective Pain Assessment for Autosomal Dominant Polycystic Kidney Disease (ADPKD): A Patient's Perspective.
    Jullie Hoggan.
      
    DOI:  https://doi.org/10.2215/CJN.0000000000000043
  2. Clin J Am Soc Nephrol. 2023 Feb 01. 18(2): 160-162
    A Step Ahead toward Measuring Pain in Autosomal Dominant Polycystic Kidney Disease (ADPKD).
    Cortney N Steele, Kristen L Nowak.
      
    DOI:  https://doi.org/10.2215/CJN.0000000000000042
  3. J Cell Sci. 2023 Feb 01. pii: jcs260565. [Epub ahead of print]136(3):
    Ciliary mechanosensation - roles of polycystins and mastigonemes.
    Peiwei Liu, Ying Liu, Jun Zhou.
      Cilia are surface-exposed organelles that provide motility and sensory functions for cells, and it is widely believed that mechanosensation can be mediated through cilia. Polycystin-1 and -2 (PC-1 and PC-2, respectively) are transmembrane proteins that can localize to cilia; however, the molecular mechanisms by which polycystins contribute to mechanosensation are still controversial. Studies detail two prevailing models for the molecular roles of polycystins on cilia; one stresses the mechanosensation capabilities and the other unveils their ligand-receptor nature. The discovery that polycystins interact with mastigonemes, the 'hair-like' protrusions of flagella, is a novel finding in identifying the interactors of polycystins in cilia. While the functions of polycystins proposed by both models may coexist in cilia, it is hoped that a precise understanding of the mechanism of action of polycystins can be achieved by uncovering their distribution and interacting factors inside cilia. This will hopefully provide a satisfying answer to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in PC-1 and PC-2. In this Review, we discuss the characteristics of polycystins in the context of cilia and summarize the functions of mastigonemes in unicellular ciliates. Finally, we compare flagella and molecular features of PC-2 between unicellular and multicellular organisms, with the aim of providing new insights into the ciliary roles of polycystins in general.
    Keywords:  Cilia; Flagella; Mastigoneme; Mechanosensation; Polycystin
    DOI:  https://doi.org/10.1242/jcs.260565
  4. Annu Rev Physiol. 2023 Feb 10. 85 425-448
    Polycystin Channel Complexes.
    Orhi Esarte Palomero, Megan Larmore, Paul G DeCaen.
      Polycystin subunits can form hetero- and homotetrameric ion channels in the membranes of various compartments of the cell. Homotetrameric polycystin channels are voltage- and calcium-modulated, whereas heterotetrameric versions are proposed to be ligand- or autoproteolytically regulated. Their importance is underscored by variants associated with autosomal dominant polycystic kidney disease and by vital roles in fertilization and embryonic development. The diversity in polycystin assembly and subcellular distribution allows for a multitude of sensory functions by this class of channels. In this review, we highlight their recent structural and functional characterization, which has provided a molecular blueprint to investigate the conformational changes required for channel opening in response to unique stimuli. We consider each polycystin channel type individually, discussing how they contribute to sensory cell biology, as well as their impact on the physiology of various tissues.
    Keywords:  ADPKD; TRP channel; autosomal dominant polycystic kidney disease; ciliopathies; gating mechanism; polycystin; primary cilia
    DOI:  https://doi.org/10.1146/annurev-physiol-031522-084334
  5. Clin J Am Soc Nephrol. 2023 Feb 01. 18(2): 154-156
    Concurrent Targeting of Vasopressin Receptor 2 and Somatostatin Receptors in Autosomal Dominant Polycystic Kidney Disease: A Promising Approach for Autosomal Dominant Polycystic Kidney Disease Treatment?
    Marie C Hogan, Tatyana V Masyuk.
      
    DOI:  https://doi.org/10.2215/CJN.0000000000000055
  6. Front Mol Biosci. 2023 ;10 1058825
    Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model.
    Xuewen Song, Wouter N Leonhard, Anish A Kanhai, Gregory R Steinberg, York Pei, Dorien J M Peters.
      Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease. Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model. Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response. Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.
    Keywords:  ADPKD; combination therapy; gene expression profiling; preclinical trial; salsalate; tolvaptan
    DOI:  https://doi.org/10.3389/fmolb.2023.1058825
  7. Case Rep Gastroenterol. 2023 Jan-Dec;17(1):17(1): 21-25
    Intraductal Papillary Mucinous Neoplasm of the Pancreas Associated with Polycystic Liver and Kidney Disease.
    Norio Yokoigawa, Yusai Kawaguchi.
      A 77-year-old man was pointed out thrombocytopenia and polycystic liver and kidney disease following hypertension and diabetes mellitus and duodenitis. He consulted to our hospital for further examination. Computed tomography (CT) showed multiple cysts in the liver and kidney and also showed cystic lesions in the pancreatic tail. The size of the tumor of pancreas was 3 cm × 4 cm. FDG-PET CT showed FDG uptake in the tumor of the pancreatic tail. It has not showed metastasis in the other organs. The examinations suggested that the cause of thrombocytopenia was infection of Helicobacter pylori or idiopathic thrombocytopenic purpura or drugs. We performed distal pancreatectomy for the tumor of pancreas. Histological findings revealed that the tumor of pancreas was invasive intraductal mucinous carcinoma. He had no recurrence for 3 months after operation. In this case, the patient with autosomal-dominant polycystic kidney disease (ADPKD) and multiple liver cysts developed IPMC. We suggest that some genetic interactions may exist between ADPKD and pancreatic carcinogenesis.
    Keywords:  Intraductal papillary mucinous neoplasm of the pancreas; Kidney disease; Polycystic liver
    DOI:  https://doi.org/10.1159/000528387
  8. J Assist Reprod Genet. 2023 Feb 11.
    Blocker displacement amplification-based genetic diagnosis for autosomal dominant polycystic kidney disease and the clinical outcomes of preimplantation genetic testing.
    Tingting Lin, Junfeng Luo, Haibing Yu, Bohao Dong, Qi Zhang, Wei Zhang, Ke Chen, Yezhou Xiang, Dongyun Liu, Guoning Huang.
       OBJECTIVE: Given that the molecular diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is complicated, we aim to apply blocker displacement amplification (BDA) on the mutational screening of PKD1 and PKD2.
    METHODS: A total of 35 unrelated families with ADPKD were recruited from the Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University (Chongqing, China), from October 2018 to October 2021. Long-range PCR followed by next-generation sequencing were applied for resequencing of PKD1 and PKD2, and the putatively disease-causative variants were verified with BDA. The effects of ADPKD on male and female infertility and the factors influencing the clinical outcomes of preimplantation genetic testing (PGT) for ADPKD were investigated.
    RESULTS: A total of 26 PKD1 variants and 5 PKD2 variants were identified, of which 13 were newly discovered. The BDA system worked effectively for eliminating the interference of pseudogenes in genetic testing of PKD1 (1-33 exons) with different concentrations of genome DNA. The females with ADPKD have no specific infertility factors, while 68.2% of the affected men were with abnormal sperm concentration and/or motility with an indefinite genotype-phenotype relationship. As for PGT, the fertilization rate of couples with the male partner having ADPKD was relatively lower compared to those with the female partner being affected. The ADPKD patients receiving PGT usually achieved high rates of live births.
    CONCLUSION: These findings expanded the variant spectrum of PKD genes and emphasized the application prospect of blocker displacement amplification on PKD1-related genetic diagnosis.
    Keywords:  ADPKD; Blocker displacement amplification; PKD1; PKD2; Preimplantation genetic testing
    DOI:  https://doi.org/10.1007/s10815-023-02722-1
  9. J Biol Chem. 2023 Feb 06. pii: S0021-9258(23)00117-5. [Epub ahead of print] 102985
    The Rab GTPase-binding protein EHBP1L1 and its interactors CD2AP/CIN85 negatively regulate the length of primary cilia via actin remodeling.
    Tomohiko Iwano, Tomoaki Sobajima, Sén Takeda, Akihiro Harada, Shin-Ichiro Yoshimura.
      Primary cilia are organelles consisting of axonemal microtubules and plasma membranes, and they protrude from the cell surface to the extracellular region and function in signal sensing and transduction. The integrity of cilia, including the length and structure, is associated with signaling functions; however, factors involved in regulating the integrity of cilia have not been fully elucidated. Here, we showed that the Rab GTPase-binding protein EHBP1L1 and its newly identified interactors CD2AP and CIN85, known as adaptor proteins of actin regulators, are involved in ciliary length control. Immunofluorescence microscopy showed that EHBP1L1 and CD2AP/CIN85 are localized to the ciliary sheath. EHBP1L1 depletion caused mislocalization of CD2AP/CIN85, suggesting that CD2AP/CIN85 localization to the ciliary sheath is dependent on EHBP1L1. Additionally, we determined that EHBP1L1- and CD2AP/CIN85-depleted cells had elongated cilia. The aberrantly elongated cilia phenotype and the ciliary localization defect of CD2AP/CIN85 in EHBP1L1-depleted cells were rescued by the expression of wild-type EHBP1L1, although this was not observed in the CD2AP/CIN85-binding deficient mutant, indicating that the EHBP1L1-CD2AP/CIN85 interaction is crucial for controlling ciliary length. Furthermore, EHBP1L1- and CD2AP/CIN85-depleted cells exhibited actin nucleation and branching defects around the ciliary base. Taken together, our data demonstrate that the EHBP1L1-CD2AP/CIN85 axis negatively regulates ciliary length via actin network remodeling around the basal body.
    Keywords:  Arp2/3 complex; Rab; actin; cytoskeleton; membrane trafficking; primary cilium
    DOI:  https://doi.org/10.1016/j.jbc.2023.102985
  10. Clin Kidney J. 2023 Feb;16(2): 355-366
    The genetic landscape of autosomal dominant polycystic kidney disease in Kuwait.
    Hamad Ali, Medhat Naim, Sarah R Senum, Ali AlSahow, Yousif Bahbahani, Mohamed Abu-Farha, Jehad Abubaker, Anwar Mohammad, Adel Al-Hunayan, Akram M Asbeutah, Mohamed Zayed, Sriraman Devarajan, Naser Hussain, Sumi Elsa John, Arshad Channanath, Thangavel Alphonse Thanaraj, Mohammad Al-Ali, Mustafa AlMousawi, Fahd Al-Mulla, Peter C Harris.
       Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal monogenic disease, characterized by bilateral accumulation of renal fluid-filled cysts leading to progressive renal volume enlargement and gradual impairment of kidney function, often resulting in end-stage renal disease. Kuwait could provide valuable genetic insights about ADPKD, including intrafamilial phenotypic variation, given its large household size. This study aims to provide a comprehensive description of the pathogenic variants linked to ADPKD in the Kuwaiti population using multiple genetic analysis modalities and to describe and analyse the ADPKD phenotypic spectrum in terms of kidney function, kidney volume and renal survival.
    Methods: A total of 126 ADPKD patients from 11 multiplex families and 25 singletons were recruited into the study. A combination of targeted next-generation sequencing (tNGS), long-range polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification were utilized for genetic diagnosis. Clinical evaluation was conducted through renal function testing and ultrasonographic kidney volume analysis.
    Results: We identified 29 ADPKD pathogenic mutations from 36 families achieving an overall molecular genetic diagnostic rate of 112/126 (88.9%), including 29/36 (80.6%) in families. A total of 28/36 (77.8%) families had pathogenic mutations in PKD1, of which 17/28 (60.7%) were truncating, and 1/36 (2.8%) had a pathogenic variant in the IFT140 gene. A total of 20/29 (69%) of the identified ADPKD mutations were novel and described for the first time, including a TSC2-PKD1 contiguous syndrome. Clinical analysis indicated that genetically unresolved ADPKD cases had no apparent association between kidney volume and age.
    Conclusion: We describe for the first time the genetic landscape of ADPKD in Kuwait. The observed genetic heterogeneity underlining ADPKD along with the wide phenotypic spectrum reveal the level of complexity in disease pathophysiology. ADPKD genetic testing could improve the care of patients through improved disease prognostication, guided treatment and genetic counselling. However, to fulfil the potential of genetic testing, it is important to overcome the hurdle of genetically unresolved ADPKD cases.
    Keywords:  IFT140; TSC2/PKD1 contiguous gene syndrome; eGFR; htTKV; polycystic kidney disease
    DOI:  https://doi.org/10.1093/ckj/sfac236
  11. Clin J Am Soc Nephrol. 2023 Feb 01. 18(2): 213-222
    Development of a Patient-Reported Outcomes Tool to Assess Pain and Discomfort in Autosomal Dominant Polycystic Kidney Disease.
    Dorothee Oberdhan, Jason C Cole, Mark J Atkinson, Holly B Krasa, Sara N Davison, Ronald D Perrone.
       BACKGROUND: Pain has been identified as a core outcome for individuals with autosomal dominant polycystic kidney disease (ADPKD), but no disease-specific pain assessment has been developed using current development methodology for patient-reported outcomes (PRO) instruments. We developed and validated an ADPKD-specific pain questionnaire: the ADPKD Pain and Discomfort Scale (ADPKD-PDS).
    METHODS: Conceptual underpinnings were drawn from literature review, concept elicitation, expert consultation, and measurement performance. In the qualitative analysis phase, concepts were elicited from focus groups of adults with ADPKD, and the resulting draft instrument was refined using cognitive debriefing interviews with individuals with ADPKD. For quantitative analysis, adults with ADPKD completed the draft instrument and other PRO tools in an online survey, and a follow-up survey was conducted 3-4 weeks later. Survey responses were analyzed for item-level descriptive statistics, latent model fit statistics, item discrimination, item- and domain-level psychometric statistics, test-retest reliability, responsiveness to change, and convergent validity.
    RESULTS: In the qualitative phase, 46 focus groups were conducted in 18 countries with 293 participants. Focus groups described three conceptually distinct types of ADPKD-related pain and discomfort (dull kidney pain, sharp kidney pain, and fullness/discomfort). In the quantitative phase, 298 adults with ADPKD completed the online survey, and 108 participants completed the follow-up survey. After iterative refinement of the instrument, latent variable measurement models showed very good fit (comparative fit and nonnormed fit indices both 0.99), as did item- and domain-level psychometric characteristics. The final ADPKD-PDS contains 20 items assessing pain severity and interference with activities over a 7-day recall period.
    CONCLUSIONS: The ADPKD-PDS is the first validated tool for systematically assessing pain and discomfort in ADPKD.
    DOI:  https://doi.org/10.2215/CJN.0000000000000034
  12. J Nephrol. 2023 Feb 08.
    Acute renal intracystic hemorrhage in patients with autosomal dominant polycystic kidney disease.
    Tatsuya Suwabe, Yoshifumi Ubara, Yuki Oba, Hiroki Mizuno, Daisuke Ikuma, Masayuki Yamanouchi, Akinari Sekine, Kiho Tanaka, Eiko Hasegawa, Junichi Hoshino, Naoki Sawa.
       BACKGROUND: Renal cyst bleeding is a frequent problem in patients with autosomal dominant polycystic kidney disease (ADPKD). However, information is still limited on its frequency, causative factors, and effects on enlargement of polycystic kidneys in ADPKD.
    METHODS: We investigated the total volume of acute renal intracystic hemorrhage and its association with total kidney volume (TKV) in a large series of patients with ADPKD on dialysis, referred for renal transcatheter arterial embolization. All patients had undergone CT scan and MRI scan before the procedure. We evaluated factors potentially associated with acute renal intracystic hemorrhage. The association between the  volume of acute renal intracystic hemorrhage and the potential predisposing and associated factors was analysed by univariable and multivariable regressions.  RESULTS: We enrolled 199 patients who underwent renal transcatheter arterial embolization from 2014 to 2018 (107 men, 92 women; mean age 59.1 ± 8.6 years). The median volume of acute renal intracystic hemorrhage was 97.3 ml (interquartile range 36.6-261.7 ml). Multivariable analysis revealed that body weight, kidney stones, systolic blood pressure, and total volume of acute renal intracystic hemorrhage were significantly associated with TKV; age, body mass index, smoking, renal cyst infection, serum alkaline phosphatase, and TKV were significantly associated with the volume of acute renal intracystic hemorrhage ; and sex, age, dialysis vintage, TKV, and total volume of acute renal intracystic hemorrhage were significantly associated with the number of microcoils required to achieve renal  transcatheter arterial embolization. Total volume of acute renal intracystic hemorrhage was significantly associated with TKV (r = 0.15, p = 0.0325) and was greater in younger patients (r= - 0.32, p < 0.0001). Total volume of acute renal intracystic hemorrhage was also correlated with the number of microcoils required for renal transcatheter arterial embolization (r = 0.23, p = 0.0012).
    CONCLUSION: Acute renal intracystic hemorrhage is frequent among ADPKD patients on dialysis, and total volume of acute renal intracystic hemorrhage significantly associated with  TKV. Total volume of acute renal intracystic hemorrhage  was greater in younger patients with higher renal artery luminal size. These results suggest that renal cyst bleeding and renal artery blood flow may synergistically accelerate the enlargement of polycystic kidneys in ADPKD patients on dialysis.
    Keywords:  Autosomal dominant polycystic kidney disease; Polycystic kidney disease; Renal cyst bleeding; Renal intracystic hemorrhage
    DOI:  https://doi.org/10.1007/s40620-022-01562-z
  13. Br J Pharmacol. 2023 Feb 11.
    Primary cilia, AKAPs and constitutive activity at the orphan G protein-coupled receptor GPR161: a tale about a tail.
    Kinjal Patel, Nicola J Smith.
      Primary cilia are non-motile antennae-like structures responsible for sensing environmental changes in most mammalian cells. Ciliary signalling is largely mediated by the Sonic Hedgehog (Shh) pathway, which acts as a master regulator of ciliary protein transit and is essential for normal embryonic development. One particularly important player in primary cilia is the orphan G protein-coupled receptor, GPR161. In this review, we introduce GPR161 in the context of Shh signalling and describe the unique features on its C-terminus such as PKA phosphorylation sites and an A-kinase anchoring protein motif, which may influence the function of the receptor, cAMP compartmentalisation and/or trafficking within primary cilia. We discuss the recent putative pairing of GPR161 and spexin-1, highlighting the additional steps needed before GPR161 could be considered 'deorphanised'. Finally, we speculate that the marked constitutive activity and unconventional regulation of GPR161 may indicate that the receptor may not require an endogenous ligand.
    Keywords:  A-kinase anchoring protein; G protein-coupled receptor; GPR161; Sonic Hedgehog; cAMP; compartmentalisation; primary cilia; protein kinase A
    DOI:  https://doi.org/10.1111/bph.16053
  14. Clin J Am Soc Nephrol. 2023 Feb 01. 18(2): 223-233
    Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial.
    TOOL Study Group
       BACKGROUND: Tolvaptan and octreotide-long-acting release (LAR) have renoprotective effects in autosomal dominant polycystic kidney disease (ADPKD) that are partially mediated by amelioration of compensatory glomerular hyperfiltration. We compared the effects of tolvaptan and octreotide-LAR combination therapy versus those of tolvaptan monotherapy in patients with ADPKD.
    METHODS: This pilot, randomized, placebo-controlled, cross-over trial primarily compared the effects of 1- and 4-week treatments with octreotide-LAR (two 20-mg i.m. injections) or placebo (two i.m. 0.9% saline solution injections) added-on tolvaptan (up to 90 and 30 mg/d) on GFR (iohexol plasma clearance) in 19 consenting patients with ADPKD referred to a clinical research center in Italy. Analyses were intention-to-treat. The local ethical committee approved the study.
    RESULTS: At 4 weeks, GFR significantly decreased by a median (interquartile range) of 3 (-1 to 5) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.01) and by 7 (3-14) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR (P=0.03). GFR changes during the two treatment periods differed by 2 (-5 to 14) ml/min per 1.73 m2 (P=0.28). At 1 week, GFR significantly decreased by 3 (0-7) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.006) and by 10 (-6 to 16) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR add-on therapy (P<0.001). GFR changes during the two treatment periods significantly differed by 3 (0-12) ml/min per 1.73 m2 (P=0.012). Total kidney volume nonsignificantly changed by 4 (-48 to 23) ml with tolvaptan and placebo (P=0.74), whereas it decreased significantly by 41 (25-77) ml with tolvaptan and octreotide-LAR (P=0.001). Changes during the two treatment periods differed by 36 (0-65) ml (P=0.01). Octreotide-LAR also attenuated (P=0.02) the aquaretic effect of tolvaptan. Treatments were well tolerated.
    CONCLUSIONS: In patients with ADPKD, octreotide-LAR added-on tolvaptan reduced GFR more effectively than octreotide-LAR and placebo. Octreotide-LAR also reduced total and cystic kidney volumes and attenuated the acquaretic effect of tolvaptan.
    CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447.
    DOI:  https://doi.org/10.2215/CJN.0000000000000049
  15. Clin Kidney J. 2023 Feb;16(2): 384-393
    Microvascular perfusion, perfused boundary region and glycocalyx shedding in patients with autosomal dominant polycystic kidney disease: results from the GlycoScore III study.
    Alexander Fuchs, Jennifer Dederichs, Sita Arjune, Polina Todorova, Fabian Wöstmann, Philipp Antczak, Anja Illerhaus, Birgit Gathof, Franziska Grundmann, Roman-Ulrich Müller, Thorsten Annecke.
       Background: Vascular abnormalities and endothelial dysfunction are part of the spectrum of autosomal dominant polycystic kidney disease (ADPKD). The mechanisms behind these manifestations, including potential effects on the endothelial surface layer (ESL) and glycocalyx integrity, remain unknown.
    Methods: Forty-five ambulatory adult patients with ADPKD were enrolled in this prospective, observational, cross-sectional, single-centre study. Fifty-one healthy volunteers served as a control group. All participants underwent real-time microvascular perfusion measurements of the sublingual microcirculation using sidestream dark field imaging. After image acquisition, the perfused boundary region (PBR), an inverse parameter for red blood cell (RBC) penetration into the ESL, was automatically calculated. Microvascular perfusion was assessed by RBC filling and capillary density. Concentrations of circulating glycocalyx components were determined by enzyme-linked immunosorbent assay.
    Results: ADPKD patients showed a significantly larger PBR compared with healthy controls (2.09 ± 0.23 µm versus 1.79 ± 0.25 µm; P < .001). This was accompanied by significantly lower RBC filling (70.4 ± 5.0% versus 77.9 ± 5.4%; P < .001) as well as a higher valid capillary density {318/mm2 [interquartile range (IQR) 269-380] versus 273/mm2 [230-327]; P = .007}. Significantly higher plasma concentrations of heparan sulphate (1625 ± 807 ng/ml versus 1329 ± 316 ng/ml; P = .034), hyaluronan (111 ng/ml [IQR 79-132] versus 92 ng/ml [82-98]; P = .042) and syndecan-1 were noted in ADPKD patients compared with healthy controls (35 ng/ml [IQR 27-57] versus 29 ng/ml [23-42]; P = .035).
    Conclusions: Dimensions and integrity of the ESL are impaired in ADPKD patients. Increased capillary density may be a compensatory mechanism for vascular dysfunction to ensure sufficient tissue perfusion and oxygenation.
    Keywords:  ADPKD; endothelium; glycocalyx; intravital microscopy; microcirculation
    DOI:  https://doi.org/10.1093/ckj/sfac229
  16. Mol Biol Cell. 2023 Feb 08. mbcE22060219
    Lithium-induced ciliary lengthening sparks Arp2/3 complex-dependent endocytosis.
    Brae M Bigge, Larissa L Dougherty, Prachee Avasthi.
      Ciliary length is highly regulated, but can be disrupted by lithium, which causes ciliary elongation across cell types and organisms. We used the algal system Chlamydomonas reinhardtii to investigate the mechanism behind lithium-induced ciliary elongation. Protein synthesis is not required for lengthening and the target of lithium, GSK3, has substrates that can influence membrane dynamics. Further, ciliary assembly requires a supply of ciliary membrane as well protein.  Lithium-treated cilia elongate normally with Brefeldin treatment, but Dynasore treatment produced defective lengthening suggesting a source of membrane from the cell surface rather than the Golgi. Genetic or chemical perturbation of the Arp2/3 complex or dynamin, required for endocytosis, blocks lithium-induced ciliary lengthening. Finally, we found an increase in Arp2/3 complex- and endocytosis-dependent actin filaments near the ciliary base upon lithium treatment. Our results identify a mechanism for lithium-mediated cilium lengthening and demonstrate the endocytic pathway for cilium membrane supply in algae is likely a conserved mechanism given lithium's conserved effects across organisms.
    DOI:  https://doi.org/10.1091/mbc.E22-06-0219
  17. Mol Biol Cell. 2023 Feb 08. mbcE22090443
    Initial ciliary assembly in Chlamydomonas requires Arp2/3 complex-dependent endocytosis.
    Brae M Bigge, Nicholas E Rosenthal, Prachee Avasthi.
      Ciliary assembly, trafficking, and regulation are dependent on microtubules, but the mechanisms of ciliary assembly also require the actin cytoskeleton. Here, we dissect subcellular roles of actin in ciliogenesis by focusing on actin networks nucleated by the Arp2/3 complex in the powerful ciliary model, Chlamydomonas. We find the Arp2/3 complex is required for the initial stages of ciliary assembly when protein and membrane are in high demand but cannot yet be supplied from the Golgi complex. We provide evidence for Arp2/3 complex-dependent endocytosis of ciliary proteins, an increase in endocytic activity upon induction of ciliary growth, and relocalization of plasma membrane proteins to newly formed cilia.
    DOI:  https://doi.org/10.1091/mbc.E22-09-0443
  18. Biochem Biophys Res Commun. 2023 Jan 31. pii: S0006-291X(23)00141-9. [Epub ahead of print]649 32-38
    Rho-kinase inhibitor restores glomerular fatty acid metabolism in diabetic kidney disease.
    Yosuke Nagai, Keiichiro Matoba, Hideji Yako, Shinji Ohashi, Kensuke Sekiguchi, Etsuko Mitsuyoshi, Kazunori Sango, Daiji Kawanami, Kazunori Utsunomiya, Rimei Nishimura.
      The small GTPase Rho and its effector Rho-kinase (ROCK) are activated in the diabetic kidney, and recent studies decade have demonstrated that ROCK signaling is an integral pathway in the progression of diabetic kidney disease. We previously identified the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism in diabetic glomeruli. However, the effect of pharmacological intervention for ROCK1 is not clear. In the present study, we show that the inhibition of ROCK1 by Y-27632 and fasudil restores fatty acid oxidation in the glomeruli. Mechanistically, these compounds optimize fatty acid utilization and redox balance in mesangial cells via AMPK phosphorylation and the subsequent induction of PGC-1α. A further in vivo study showed that the inhibition of ROCK1 suppressed the downregulation of the fatty acid oxidation-related gene expression in glomeruli and mitochondrial fragmentation in the mesangial cells of db/db mice. These observations indicate that ROCK1 could be a promising therapeutic target for diabetic kidney disease through a mechanism that improves glomerular fatty acid metabolism.
    Keywords:  Diabetic kidney disease; Fasudil; Fatty acid metabolism; Rho-kinase
    DOI:  https://doi.org/10.1016/j.bbrc.2023.01.088
  19. J Inflamm Res. 2023 ;16 373-380
    Shorter Cilia Length and Aberrant Ciliated Marker DNAI1 in Allergic Rhinitis.
    Suizi Zhou, Yitong Liu, Yueying Yang, Hongming Huang, Qianhui Qiu.
       Purpose: This study aimed to investigate whether the impaired ciliary length and aberrant ciliary ultrastructure marker, dynein axonemal intermediate chain 1 (DNAI1), are important pathological characteristics in nasal mucosa from patients with allergic rhinitis (AR).
    Patients and Methods: Biopsies were taken from the inferior turbinate (IT) of controls (n = 20) and patients with AR (n = 20). The ciliary length and the DNAI1 location patterns were assessed by using immunofluorescent staining. Three patterns of DNAI1 localization were defined using a semi-quantitative scoring system: normal (N), partial (P) and absence (A). Every individual section was assigned a score between 0 and 2 in each high-power field (5 fields per sample). The score of 0 = pattern N >70%; 1 = patterns N + P >70%; and 2 = pattern A ≥30%. The receiver operating characteristic (ROC) curve was used to evaluate the predicted value of DNAI1 score for AR.
    Results: The ciliary length was reduced by 33.3% in patients with AR compared with controls (P < 0.0001). The higher DNAI1 score was found in the AR group, with a median (first and third quartile) of 0.9 (0.4 and 1.08), which was 0.1 (0 and 0.76) in the control group (P = 0.0071). The ROC of DNAI1 was calculated based on the area under the curve of 0.74 (P = 0.0094). The cutoff value of ROC was 0.5833, with a sensitivity and specificity of 70%.
    Conclusion: These results suggested that the shorter ciliary length and aberrant localization of DNAI1 are potentially important pathological characteristics of the allergic nasal mucosa. The aberrant localization of DNAI1 may provide a novel candidate target for clinical management of AR.
    Keywords:  DNAI1; allergic rhinitis; biomarker; cilia length; ciliated marker
    DOI:  https://doi.org/10.2147/JIR.S393025
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