bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023‒02‒26
fifteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

  1. Trends Mol Med. 2023 Feb 15. pii: S1471-4914(23)00029-1. [Epub ahead of print]
      Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease caused by mutations in PKD1 and PKD2 that encode polycystin 1 (PC1) and polycystin 2 (PC2). PC1/2 localize to cilia of renal epithelial cells, and their function is believed to embody an inhibitory activity that suppresses the cilia-dependent cyst activation (CDCA) signal. Consequently, PC deficiency results in activation of CDCA and stimulates cyst growth. Recently, re-expression of PCs in established cysts has been shown to reverse PKD. Thus, the mode of action of PCs resembles a 'counterbalance in cruise control' to maintain lumen diameter within a designated range. Herein we review recent studies that point to novel arenas for future PC research with therapeutic potential for ADPKD.
    Keywords:  ADPKD; CDCA; cation channel; cilia; lumen diameter control; polycystin
  2. Sci Rep. 2023 Feb 20. 13(1): 2952
      Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P < 0.001), and less likely to have a family history of ADPKD (26.1% vs. 74.6%; P < 0.001), a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%; P < 0.001), or progression to CKD stage 3 or stage 5 (P < 0.001). Patients with atypical polycystic kidney disease by imaging represent a distinct prognostic group with a low likelihood of progression to CKD.
  3. Rozhl Chir. 2023 ;102(1): 11-16
      INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that leads to chronic renal failure in about half of patients. It is a multisystemic disease with a predominance of kidney involvement, which significantly worsens the patient's health. Controversial issues include the indication and the timing and technique of nephrectomy of native polycystic kidneys.METHODS: A retrospective observational study focused on the surgical aspects of patients with ADPKD who underwent native nephrectomy at our institution. The group included patients operated on in the period 1/1/2000-31/12/2020. A total of 115 patients with ADPKD were enrolled (14.7% of all transplant recipients). We evaluated the basic demographic data, type of surgery, indications and complications in this group.
    RESULTS: Native nephrectomy was performed in 68 out of a total of 115 (59%) patients. Unilateral nephrectomy was done in 22 (32%) patients and bilateral in 46 (68%). The most common indications were infections (42 patients, 36%), pain (31 patients, 27%), hematuria (14 patients, 12%), gastrointestinal reasons (1 patient, 1%), respiratory reasons (1 patient, 1%), obtaining a site for transplantation (17 patients, 15%) and suspected tumor (5 patients, 4%).
    CONCLUSION: Native nephrectomy is recommended in symptomatic kidneys, or in asymptomatic kidneys when it is necessary to obtain a place for kidney transplantation, and in kidneys where a tumor is suspected.
    Keywords:  ADPKD; autosomal dominant polycystic kidney disease; kidney transplantation; native nephrectomy
  4. Kidney Int. 2023 Feb 18. pii: S0085-2538(23)00122-9. [Epub ahead of print]
      Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator, adenosine monophosphate stimulated protein kinase (AMPK), has been implicated as a promising new therapeutic target. To address this hypothesis, we determined the effects of a potent and selective clinical stage direct allosteric AMPK activator, PXL770, in canine and patient-derived 3D cyst models and an orthologous mouse model of ADPKD. PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. In an inducible, kidney epithelium-specific Pkd1 knockout mouse model, PXL770 produced kidney AMPK pathway engagement, prevented the onset of kidney failure (reducing blood urea by 47%), decreased cystic index by 26% and lowered the kidney weight to body weight ratio by 35% compared to untreated control Pkd1 knockout mice. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication.
    Keywords:  ADPKD; Chronic kidney disease; animal model; fibrosis; inflammation; mitochondria; renal pathology; uremia
  5. Clin Kidney J. 2022 Aug;15(8): 1553-1561
      Background: On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data.Methods: This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD.
    Results: Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411).
    Conclusions: In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.
    Keywords:  Risk Evaluation and Mitigation Strategy (REMS); autosomal dominant polycystic kidney disease (ADPKD); cystatin C; drug-induced liver injury (DILI); liver safety; post marketing surveillance; tolvaptan
  6. SLAS Technol. 2023 Feb 17. pii: S2472-6303(23)00011-0. [Epub ahead of print]
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and is characterized by the formation of renal cysts and the eventual development of end-stage kidney disease. One approach to treating ADPKD is through inhibition of the mammalian target of rapamycin (mTOR) pathway, which has been implicated in cell overproliferation, contributing to renal cyst expansion. However, mTOR inhibitors, including rapamycin, everolimus, and RapaLink-1, have off-target side effects including immunosuppression. Thus, we hypothesized that the encapsulation of mTOR inhibitors in drug delivery carriers that target the kidneys would provide a strategy that would enable therapeutic efficacy while minimizing off-target accumulation and associated toxicity. Toward eventual in vivo application, we synthesized cortical collecting duct (CCD) targeted peptide amphiphile micelle (PAM) nanoparticles and show high drug encapsulation efficiency (>92.6 %). In vitro analysis indicated that drug encapsulation into PAMs enhanced the anti-proliferative effect of all three drugs in human CCD cells. Analysis of in vitro biomarkers of the mTOR pathway via western blotting confirmed that PAM encapsulation of mTOR inhibitors did not reduce their efficacy. These results indicate that PAM encapsulation is a promising way to deliver mTOR inhibitors to CCD cells and potentially treat ADPKD. Future studies will evaluate the therapeutic effect of PAM-drug formulations and ability to prevent off-target side effects associated with mTOR inhibitors in mouse models of ADPKD.
    Keywords:  ADPKD; MTOR; Micelles; Rapalogs; Targeted
  7. Pediatr Nephrol. 2023 Feb 22.
      BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is among the most common inherited kidney diseases. Hypertension is a frequent cardiovascular manifestation, especially in adults, but elevated blood pressure is also found in children and adolescents. Acknowledgment of pediatric hypertension early is critical, as it can result in serious complications long-term if left undiagnosed.OBJECTIVE: We aim to identify the influence of hypertension on cardiovascular outcomes, mainly left ventricular hypertrophy, carotid intima media thickness, and pulse wave velocity.
    METHODS: We performed an extensive search on Medline, Embase, CINAHL, and Web of Science databases through March 2021. Original studies with a mix of retrospective, prospective, case-control studies, cross sectional studies, and observational studies were included in the review. There was no restriction on age group.
    RESULTS: The preliminary search yielded 545 articles with 15 articles included after inclusion and exclusion criteria. In this meta-analysis, LVMI (SMD: 3.47 (95% CI: 0.53-6.41)) and PWV (SMD: 1.72 (95% CI: 0.08-3.36)) were found to be significantly higher in adults with ADPKD compared to non-ADPKD; however, CIMT was not found to be significantly different. Also, LVMI was observed to be significantly higher among hypertensive adults with ADPKD (n = 56) as compared to adults without ADPKD (SMD: 1.43 (95% CI: 1.08-1.79)). Fewer pediatric studies were available with heterogeneity among patient populations and results.
    CONCLUSIONS: Adult patients with ADPKD were found to have worse indicators of cardiovascular outcomes, including LVMI and PWV, as compared to non-ADPKD. This study demonstrates the importance of identifying and managing hypertension, especially early, in this population. Further research, particularly in younger patients, is necessary to further elucidate the relationship between hypertension in patients with ADPKD and cardiovascular disease.
    Keywords:  ADPKD; Cardiovascular; Carotid intima media thickness; Hypertension; Left ventricular mass index; Pediatrics; Pulse wave velocity
  8. bioRxiv. 2023 Feb 15. pii: 2023.02.15.528685. [Epub ahead of print]
      Human islet primary cilia are vital glucose-regulating organelles whose structure remains uncharacterized. Scanning electron microscopy (SEM) is a useful technique for studying the surface morphology of membrane projections like primary cilia, but conventional sample preparation does not reveal the sub-membrane axonemal structure which holds key implications for cilia function. To overcome this challenge, we combined SEM with membrane-extraction techniques to examine cilia in native human islets. Our data show well-preserved cilia subdomains which demonstrate both expected and unexpected ultrastructural motifs. Morphometric features were quantified when possible, including axonemal length and diameter, microtubule conformations and chirality. We further describe a novel ciliary ring, a structure that may be a specialization in human islets. Key findings are correlated with fluorescence microscopy and interpreted in the context of cilia function as a cellular sensor and communications locus in pancreatic islets.
  9. J Pharmacol Sci. 2023 Mar;pii: S1347-8613(23)00001-4. [Epub ahead of print]151(3): 148-155
      The cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB)-glycogen synthase kinase 3β (GSK3β) signaling pathway was reported to be involved in the progression of autosomal dominant polycystic kidney diseases (ADPKD). We designed and synthesized pyrrole-imidazole (PI) polyamides as novel gene-silencers to prevent binding of CREB on the GSK3β gene promoter and examined the effects of the PI polyamides on proliferation and cyst formation of mouse collecting duct M1 cells. The GSK3β PI polyamides significantly inhibited expression of GSK3β mRNA in M1 cells with forskolin. To obtain cells as collecting ducts from ADPKD, the PKD1 gene was knocked down by shRNA. Lower concentrations of forskolin significantly stimulated proliferation of PKD1 knock-down M1 cells, whereas GSK3β PI polyamide significantly inhibited proliferation of PKD1 knock-down M1 cells with forskolin. Stimulation with forskolin for 5 days induced enlargement of cysts from PKD1 knock-down M1 cells. GSK3β PI polyamides significantly suppressed the enlargement of cysts with forskolin stimulation in PKD1 knock-down M1 cells. Thus, the present study showed that transcriptional suppression of the GSK3β gene by PI polyamides targeting the binding of CREB inhibited the proliferation and cyst formation of PKD1 knock-down M1 cells. The GSK3β PI polyamides may potentially be novel medicines for ADPKD.
    Keywords:  ADPKD; Forskolin; GSK3β; PI polyamide; cAMP
  10. Clin Kidney J. 2022 Nov;15(11): 2063-2071
      Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of kidney failure worldwide. However, its impact on quality-of-life has not been systematically explored.Methods: The CYSTic-QoL study was an observational study designed to study quality-of-life in adult European ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A total of 465 patients were recruited from six expert European centres with baseline data recorded, including health-related quality-of-life (HRQoL), incorporating a Kidney Disease QoL short form questionnaire (KDQoL-SF, version 1.3), magnetic resonance imaging (MRI) for total kidney volume (TKV) measurements and DNA for genotyping. The cohort was stratified by baseline eGFR, TKV or genotype and correlated with HRQoL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the RAND organization. For 36-item short form values, mean centre scores were normalized to their native populations.
    Results: The mean age of participants was 43 years and 55% were female, with a mean eGFR of 77 mL/min/1.73 m2 and height-adjusted TKV (ht-TKV) of 849 mL/min; 66% had PKD1 pathogenic variants. ADPKD patients uniformly reported decreased general health and less energy, with the majority also experiencing poorer physical, mental or emotional health and limitations in social functioning. A total of 32.5% of participants experienced flank pain, which was significantly and negatively correlated with the majority of KDQoL-SF subscales by multivariate analysis. Higher ht-TKV and lower eGFR were negatively associated with decreased energy and poorer physical health, respectively, although not with flank pain.
    Conclusion: ADPKD patients suffer from significantly decreased QoL in multiple domains, exacerbated particularly by chronic pain.
    Keywords:  ADPKD; kidney function; pain; quality-of-life; total kidney volume
  11. bioRxiv. 2023 Feb 16. pii: 2023.02.15.528715. [Epub ahead of print]
      Ependymal cells, lining brain ventricular walls, display tufts of cilia that beat in concert promoting laminar Cerebrospinal fluid (CSF) flow within brain ventricles. The ciliary axonemes of multiciliated ependymal cells display a 9+2 microtubule array common to motile cilia. Dyneins and kinesins are ATPase microtubule motor proteins that promote the rhythmic beating of cilia axonemes. Despite common consensus about the importance of axonemal dynein motor proteins, little is known about how Kinesin motors contribute to cilia motility. Here, we define the function of Kinesin family member 6 (Kif6) using a mutation that lacks a highly conserved C-terminal tail domain ( Kif6 p.G555fs ) and which displays progressive hydrocephalus in mice. An analogous mutation was isolated in a proband displaying macrocephaly, hypotonia, and seizures implicating an evolutionarily conserved function for Kif6 in neurodevelopment. We find that loss of Kif6 function caused decreased ependymal cilia motility and subsequently decreased fluid flow on the surface of brain ventricular walls. Kif6 protein was localized at ependymal cilia and displayed processive motor movement (676 nm/s) on microtubules in vitro . Loss of the Kif6 C-terminal tail domain did not affect the initial ciliogenesis in vivo , but did result in defects in cilia orientation, the formation of robust apical actin networks, and stabilization of basal bodies at the apical surface. This suggests a novel role for the Kif6 motor in maintenance of ciliary homeostasis of ependymal cells.Summary statement: We found that Kif6 is localized to the axonemes of ependymal cells. In vitro analysis shows that Kif6 moves on microtubules and that its loss mice decrease cilia motility and cilia-driven flow, resulting in hydrocephalus.
  12. Cell Death Differ. 2023 Feb 22.
      Elevated levels of PDLIM3 expression are frequently detected in sonic hedgehog (SHH) group of medulloblastoma (MB). However, the possible role of PDLIM3 in MB tumorigenesis is still unknown. Here, we found that PDLIM3 expression is necessary for hedgehog (Hh) pathway activation in MB cells. PDLIM3 is present in primary cilia of MB cells and fibroblasts, and such cilia localization is mediated by the PDZ domain of PDLIM3 protein. Deletion of PDLIM3 significantly compromised cilia formation and interfered the Hh signaling transduction in MB cells, suggesting that PDLIM3 promotes the Hh signaling through supporting the ciliogenesis. PDLIM3 protein physically interacts with cholesterol, a critical molecule for cilia formation and hedgehog signaling. The disruption of cilia formation and Hh signaling in PDLIM3 null MB cells or fibroblasts, was significantly rescued by treatment with exogenous cholesterol, demonstrating that PDLIM3 facilitates the ciliogenesis through cholesterol provision. Finally, deletion of PDLIM3 in MB cells significantly inhibited their proliferation and repressed tumor growth, suggesting that PDLIM3 is necessary for MB tumorigenesis. Our studies elucidate the critical functions of PDLIM3 in the ciliogenesis and Hh signaling transduction in SHH-MB cells, supporting to utilize PDLIM3 as a molecular marker for defining SHH group of MB in clinics.
  13. J Am Soc Nephrol. 2023 Jan 26.
      BACKGROUND: G protein-coupled receptor kinase 4 (GRK4) is considered a central regulator of blood pressure through phosphorylation of renal dopaminergic receptors and subsequent modulation of sodium excretion. Several nonsynonymous genetic variants of GRK4 have been only partially linked to hypertension, although these variants demonstrate elevated kinase activity. However, some evidence suggests that function of GRK4 variants may involve more than regulation of dopaminergic receptors alone. Little is known about the effects of GRK4 on cellular signaling, and it is also unclear whether or how altered GRK4 function might affect kidney development.METHODS: To better understand the effect of GRK4 variants on the functionality of GRK4 and GRK4's actions in cellular signaling during kidney development, we studied zebrafish, human cells, and a murine kidney spheroid model.
    RESULTS: Zebrafish depleted of Grk4 develop impaired glomerular filtration, generalized edema, glomerular cysts, pronephric dilatation, and expansion of kidney cilia. In human fibroblasts and in a kidney spheroid model, GRK4 knockdown produced elongated primary cilia. Reconstitution with human wild-type GRK4 partially rescues these phenotypes. We found that kinase activity is dispensable because kinase-dead GRK4 (altered GRK4 that cannot result in phosphorylation of the targeted protein) prevented cyst formation and restored normal ciliogenesis in all tested models. Hypertension-associated genetic variants of GRK4 fail to rescue any of the observed phenotypes, suggesting a receptor-independent mechanism. Instead, we discovered unrestrained mammalian target of rapamycin signaling as an underlying cause.
    CONCLUSIONS: These findings identify GRK4 as novel regulator of cilia and of kidney development independent of GRK4's kinase function and provide evidence that the GRK4 variants believed to act as hyperactive kinases are dysfunctional for normal ciliogenesis.
  14. Biol Open. 2023 02 15. pii: bio059719. [Epub ahead of print]12(2):
      The growth and development of healthy tissues is dependent on the construction of a highly specialised extracellular matrix (ECM) to provide support for cell growth and migration and to determine the biomechanical properties of the tissue. These scaffolds are composed of extensively glycosylated proteins which are secreted and assembled into well-ordered structures that can hydrate, mineralise, and store growth factors as required. The proteolytic processing and glycosylation of ECM components is vital to their function. These modifications are under the control of the Golgi apparatus, an intracellular factory hosting spatially organised, protein-modifying enzymes. Regulation also requires a cellular antenna, the cilium, which integrates extracellular growth signals and mechanical cues to inform ECM production. Consequently, mutations in either Golgi or ciliary genes frequently lead to connective tissue disorders. The individual importance of each of these organelles to ECM function is well-studied. However, emerging evidence points towards a more tightly linked system of interdependence between the Golgi, cilium and ECM. This review examines how the interplay between all three compartments underpins healthy tissue. As an example, it will look at several members of the golgin family of Golgi-resident proteins whose loss is detrimental to connective tissue function. This perspective will be important for many future studies looking to dissect the cause and effect of mutations impacting tissue integrity.
    Keywords:  Ciliopathies; Cilium; Extracellular matrix; Golgi; Golgin; Tissue