bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒01‒24
fourteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

  1. J Med Econ. 2021 Jan 19. 1
      AIM: To build upon previous outdated studies by comprehensively assessing the direct healthcare burden of autosomal dominant polycystic kidney disease (ADPKD).MATERIALS AND METHODS: Patients with ≥2 diagnoses for ADPKD (ADPKD cohort) were identified in the US fee-for-use IBM Truven Health Analytics MarketScan® Commercial Claims and Encounters and IBM Truven Health Analytics MarketScan® Medicare Supplemental databases (01/01/2015-12/31/2017) and matched (1:3) to controls without ADPKD (non-ADPKD cohort). The index date was the last calendar date followed by 12 months continuous enrollment (study period). Patients with ADPKD were stratified into one of seven mutually exclusive groups based on chronic kidney disease (CKD) stages (I-V), end-stage renal disease requiring renal replacement therapy (ESRD-RRT), and unknown stage.
    RESULTS: During the 12-month study period, patients with ADPKD incurred significantly higher total healthcare costs than those without ADPKD (mean cost difference=$22,879 per patient per year [PPPY]; p < 0.001). Besides CKD stages I and II, total healthcare cost differences increased as patients progressed beyond CKD stage III, with the greatest difference observed among patients with ESRD-RRT. Total healthcare cost differences between cohorts were more pronounced in subgroups of patients with hypertension ($29,347) and with high risk of rapid progression ($39,976). Similar results were observed in the Medicare Supplemental population, with a total mean cost difference of $42,694 PPPY (p < 0.001); cost difference was also higher in the hypertension ($46,461 PPPY) and high risk of rapid progression ($45,708 PPPY) subgroups.
    LIMITATIONS: Results may not be representative of the overall ADPKD US population; CKD stage was based on diagnosis and procedure codes; criteria used to identify ADPKD at risk of rapid progression did not rely on laboratory values; there may be billing inaccuracies and omissions in health insurance claims data.
    CONCLUSION: This study demonstrated the substantial healthcare costs associated with ADPKD, which increased as patients progressed through more severe CKD stages.
    Keywords:  H - Public Economics; H00 – General; H5 - National Government Expenditures and Related Policies; H50 – General; H51 - Government Expenditures and Health; I - Health, Education, and Welfare; I1 – Health; I15 - Health and Economic Development; Medicare; autosomal dominant polycystic kidney disease; commercial; healthcare costs; rapid progression
  2. Pediatr Nephrol. 2021 Jan 21.
      Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are characterized by bilateral cystic kidney disease leading to progressive kidney function decline. These diseases also have distinct liver manifestations. The range of clinical presentation and severity of both ADPKD and ARPKD is much wider than was once recognized. Pediatric and adult nephrologists are likely to care for individuals with both diseases in their lifetimes. This article will review genetic, clinical, and imaging predictors of kidney and liver disease progression in ADPKD and ARPKD and will briefly summarize pharmacologic therapies to prevent progression.
    Keywords:  Children; Outcomes; Polycystic kidney disease; Progression; Stage 5 chronic kidney disease
  3. Clin Exp Nephrol. 2021 Jan 20.
      BACKGROUND: Tolvaptan slowed the rates of total kidney volume (TKV) growth and renal function decline over a 3-year period in patients with autosomal dominant polycystic kidney disease (ADPKD) enrolled in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial (NCT00428948). In this post hoc analysis of Japanese patients from TEMPO 3:4, we evaluated whether the effects of tolvaptan on TKV and on renal function are interrelated.METHODS: One hundred and forty-seven Japanese patients from TEMPO 3:4 were included in this analysis (placebo, n = 55; tolvaptan, n = 92). Tolvaptan-treated patients were stratified into the responder group (n = 37), defined as tolvaptan-treated patients with a net decrease in TKV from baseline to year 3, and the non-responder group (n = 55), defined as tolvaptan-treated patients with a net increase in TKV.
    RESULTS: Mean changes during follow-up in the placebo, responder, and non-responder groups were 16.99%, - 8.33%, and 13.95%, respectively, for TKV and - 12.61, - 8.47, and - 8.58 mL/min/1.73 m2, respectively, for estimated glomerular filtration rate (eGFR). Compared with the placebo group, eGFR decline was significantly slowed in both the responder and non-responder groups (P < 0.05).
    CONCLUSION: Tolvaptan was effective in slowing eGFR decline, regardless of TKV response, over 3 years in patients with ADPKD in Japan. Treatment with tolvaptan may have beneficial effects on slowing of renal function decline even in patients who have not experienced a reduction in the rate of TKV growth by treatment with tolvaptan.
    Keywords:  Autosomal dominant polycystic kidney disease; Glomerular filtration rate; Japan; Tolvaptan; Total kidney volume
  4. Methods Mol Biol. 2021 ;2216 369-382
      Renal length and volume are important parameters in the clinical assessment of patients with diabetes mellitus, kidney transplants, or renal artery stenosis. Kidney size is used in primary diagnostics to differentiate between acute (rather swollen kidneys) and chronic (rather small kidney) pathophysiology. Total kidney volume is also an established biomarker in studies for the treatment of autosomal dominant polycystic kidney disease (ADPKD). There are several factors influencing kidney size, and there is still a debate on the value of the measured kidney size in terms of renal function or cardiovascular risk. The renal volume is most often calculated by measuring the three axes of the kidney, on the assumption that the organ resembles an ellipsoid. By default, the longitudinal and transverse diameters of the kidney are measured. In animal models renal length and volume1 are also important parameters in the assessment of organ rejection after transplantation and in determination of kidney failure due to renal artery stenosis, recurrent urinary tract infections, or diabetes mellitus. In general total kidney volume (TKV) is a valuable parameter for predicting prognosis and monitoring disease progression in animal models of human diseases like polycystic kidney disease (PKD) or acute kidney injury (AKI) and chronic kidney disease (CKD).This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol is complemented by two separate chapters describing the basic concept and experimental procedure.
    Keywords:  Kidney; Magnetic resonance imaging (MRI); Mice; Rats; T1; T2; Volume
  5. J Endourol Case Rep. 2020 ;6(4): 353-357
      Background: Autosomal dominant polycystic kidney disease (ADPKD) is most common potentially lethal cystic disease occurring in ∼1 in 1000 live births. It is an important cause of end-stage renal disease, which occurs in 75% of patients by the age of 70 years. APDPKD is a systemic disease with involvement of multiple extrarenal organs. Incidence of renal cell cancer in ADPKD is no more than in normal population. High index of suspicion is required due to gross distortion of renal architecture. Case Presentation: We report a 56-year male, known case of ADPKD on maintenance hemodialysis presenting with hematuria. On evaluation, he was diagnosed with bilateral renal masses on contrast imaging. Bilateral laparoscopic nephrectomy was performed and specimen was retrieved from pfannenstiel incision. Histology showed papillary renal cancer in left kidney and oncocytoma in right kidney with negative margins. Conclusion: Minimally invasive surgery in ADPKD with renal mass is challenging due to space constraints and large size kidneys. However, laparoscopic approach is a feasible option with minimal morbidity, less pain, and speedy recovery, specially in chronic kidney disease patients already immunocompromised status.
    Keywords:  ADPKD; laparoscopic; nephrectomy; renal cell cancer
  6. Proc (Bayl Univ Med Cent). 2020 Nov 16. 34(1): 166-168
      Turner syndrome is a chromosomal disorder that involves multiple organ systems and is typically associated with short stature. A multidisciplinary approach with regular screening and surveillance is key to managing this condition's multiple comorbidities. We present a case of a young girl with Turner syndrome and associated short stature on growth hormone treatment who presented with cystic renal disease found to be autosomal dominant kidney disease. We propose reevaluation of renal screening guidelines in this population due to the potential association of growth hormone and cyst proliferation.
    Keywords:  Growth hormone; PKD1 mutation; Turner syndrome; polycystic kidney disease
  7. Ren Fail. 2021 Dec;43(1): 223-230
      INTRODUCTION: The activation of the sympathetic nervous system, which usually leads to a swift surge in blood pressure in the morning hours (MBPS) may be the cause of left ventricular hypertrophy (LVH) and endothelial dysfunction (ED) in early autosomal dominant polycystic kidney disease (ADPKD) patients. We studied the association between MBPS and LVH in ADPKD patients with preserved renal functions.METHODS: Patients with ADPKD with preserved renal functions were enrolled. Prewaking MBPS was calculated using ambulatory blood pressure monitoring. The patients were categorized as MBPS (≥median) and non-MBPS (<median). Left ventricular mass index (LVMI), endothelial-dependent dilatation (FMD, %), and carotid intima-media thickness (CIMT) evaluated.
    RESULTS: Fifty-six patients (30 females and 26 males) were enrolled. Gender distribution was similar-among-the-groups. The mean age was higher in the MBPS group (50.1 ± 13 vs 37.3 ± 10.3). Urinary albumin (49.5 vs 16 mg/g creatinine, p < 0.001), hs-CRP (0.59 vs 0.37 mg/dl, p = 0.045) LVMI (124 ± 27.7 vs 95.2 ± 19.7 g/m2, p < 0.001) and mean awake SBP surge was higher (42 vs 20 mmHg, p < 0.001) and FMD (%) was lower (14.4 ± 6.6 vs 18.9 ± 5.7, p = 0.009) in MBPS group. In the binary logistic regression analysis, the presence of MBPS in model 1 (OR: 6.625, 95% CI [1.048-41.882] p = 0.044), and age in model 2 (OR: 1.160, 95% CI [1.065-1.263] p = 0.001) were the only independent determinant of LVH.
    CONCLUSIONS: MBPS seems to be an important and independent determinant of LVH in ADPKD patients with preserved renal functions. It may be worth assessing the effect of reduction in MBPS as a new therapeutic target to prevent LVH in-patients-with-ADPKD.
    Keywords:  Autosomal dominant polycystic kidney disease; endothelial dysfunction; left ventricular hypertrophy; morning blood pressure surge
  8. J Cell Biol. 2021 Feb 01. pii: e202003149. [Epub ahead of print]220(2):
      Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55-/- mice display clinical manifestations of Meckel-Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55-/- mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel-Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.
  9. Eur J Hum Genet. 2021 Jan 16.
      Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.
  10. Development. 2021 Jan 20. pii: dev.194787. [Epub ahead of print]
      Stem cells are maintained in specific niches that strictly regulate their proliferation and differentiation for proper tissue regeneration and renewal. Molecular oxygen (O2) is an important component of the niche microenvironment, but little is known about how O2 governs epithelial stem cell (ESC) behavior. Here, we demonstrate that O2 plays a critical role in regulating the proliferation of ESCs using the continuously growing mouse incisors. We have revealed that slow cycling cells in the niche are maintained under relatively hypoxic conditions compared with actively proliferating cells, based on the blood vessel distribution and metabolic status. Mechanistically, we have demonstrated that, during Hypoxia, HIF1α up-regulation activates the RhoA signal, thereby promoting cortical actomyosin and stabilizing adherens junction complex, including Merlin. This leads to the cytoplasmic retention of YAP/TAZ to attenuate cell proliferation. These results shed light on the biological significance of blood-vessel geometry and the signaling mechanism through microenvironmental O2 to orchestrate ESC behavior, providing a novel molecular basis for the microenvironmental O2-mediated stem cell regulation during tissue development and renewal.
    Keywords:  Actomyosin; Epithelial stem cells; Oxygen; RhoA; Rodent incisor; YAP/TAZ
  11. J Biol Chem. 2020 Dec 11. pii: S0021-9258(17)50588-8. [Epub ahead of print]295(50): 16920-16928
      Gα proteins promote dynamic adjustments of cell shape directed by actin-cytoskeleton reorganization via their respective RhoGEF effectors. For example, Gα13 binding to the RGS-homology (RH) domains of several RH-RhoGEFs allosterically activates these proteins, causing them to expose their catalytic Dbl-homology (DH)/pleckstrin-homology (PH) regions, which triggers downstream signals. However, whether additional Gα proteins might directly regulate the RH-RhoGEFs was not known. To explore this question, we first examined the morphological effects of expressing shortened RH-RhoGEF DH/PH constructs of p115RhoGEF/ARHGEF1, PDZ-RhoGEF (PRG)/ARHGEF11, and LARG/ARHGEF12. As expected, the three constructs promoted cell contraction and activated RhoA, known to be downstream of Gα13. Intriguingly, PRG DH/PH also induced filopodia-like cell protrusions and activated Cdc42. This pathway was stimulated by constitutively active Gαs (GαsQ227L), which enabled endogenous PRG to gain affinity for Cdc42. A chemogenetic approach revealed that signaling by Gs-coupled receptors, but not by those coupled to Gi or Gq, enabled PRG to bind Cdc42. This receptor-dependent effect, as well as CREB phosphorylation, was blocked by a construct derived from the PRG:Gαs-binding region, PRG-linker. Active Gαs interacted with isolated PRG DH and PH domains and their linker. In addition, this construct interfered with GαsQ227L's ability to guide PRG's interaction with Cdc42. Endogenous Gs-coupled prostaglandin receptors stimulated PRG binding to membrane fractions and activated signaling to PKA, and this canonical endogenous pathway was attenuated by PRG-linker. Altogether, our results demonstrate that active Gαs can recognize PRG as a novel effector directing its DH/PH catalytic module to gain affinity for Cdc42.
    Keywords:  ARHGEF11; Cdc42; DH/PH catalytic module; G protein–coupled receptor (GPCR); Galpha-s; Gαs; PDZ-RhoGEF; PDZ-RhoGEF (PRG); Rho (Rho GTPase); Rho GTPases; Rho guanine nucleotide exchange factor (RhoGEF); cell signaling; cell signaling GPCR; guanine nucleotide exchange factor (GEF); heterotrimeric G protein
  12. J Biol Chem. 2020 Dec 06. pii: S0021-9258(20)00128-3. [Epub ahead of print]296 100136
      To migrate, cells assume a polarized morphology, extending forward with a leading edge with their trailing edge retracting back toward the cell body. Both cell extension and retraction critically depend on the organization and dynamics of the actin cytoskeleton, and the small, monomeric GTPases Rac and Rho are important regulators of actin. Activation of Rac induces actin polymerization and cell extension, whereas activation of Rho enhances acto-myosin II contractility and cell retraction. To coordinate migration, these processes must be carefully regulated. The myosin Myo9b, a Rho GTPase-activating protein (GAP), negatively regulates Rho activity and deletion of Myo9b in leukocytes impairs cell migration through increased Rho activity. However, it is not known whether cell motility is regulated by global or local inhibition of Rho activity by Myo9b. Here, we addressed this question by using Myo9b-deficient macrophage-like cells that expressed different recombinant Myo9b constructs. We found that Myo9b accumulates in lamellipodial extensions generated by Rac-induced actin polymerization as a function of its motor activity. Deletion of Myo9b in HL-60-derived macrophages altered cell morphology and impaired cell migration. Reintroduction of Myo9b or Myo9b motor and GAP mutants revealed that local GAP activity rescues cell morphology and migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration.
    Keywords:  HL-60 cells; Myo9b; Rac1; RhoA; RhoGAP; actin; cell migration; lamellipodia; macrophages; myosin
  13. J Biol Chem. 2021 Jan 13. pii: S0021-9258(21)00058-2. [Epub ahead of print] 100290
      Rho/Ras family small GTPases are known to regulate numerous cellular processes, including cytoskeletal reorganization, cell proliferation, and cell differentiation. These processes are also controlled by Ca2+, and consequently, crosstalk between these signals is considered likely. However, systematic quantitative evaluation has not yet been reported. To fill this gap, we constructed optogenetic tools to control the activity of small GTPases (RhoA, Rac1, Cdc42, Ras, Rap, and Ral) using an improved light-inducible dimer system (iLID). We characterized these optogenetic tools with genetically encoded red fluorescence intensity-based small GTPase biosensors and confirmed these optogenetic tools' specificities. Using these optogenetic tools, we investigated calcium mobilization immediately after small GTPase activation. Unexpectedly, we found that a transient intracellular calcium elevation was specifically induced by RhoA activation in RPE1 and HeLa cells. RhoA activation also induced transient intracellular calcium elevation in MDCK and HEK293T cells, suggesting that generally RhoA induces calcium signaling. Interestingly, the molecular mechanisms linking RhoA activation to calcium increases were shown to be different among the different cell types: In RPE1 and HeLa cells, RhoA activated phospholipase C epsilon (PLCε) at the plasma membrane, which in turn induced Ca2+ release from the endoplasmic reticulum (ER). The RhoA-PLCε axis induced calcium-dependent NFAT nuclear translocation, suggesting it does activate intracellular calcium signaling. Conversely, in MDCK and HEK293T cells, RhoA-ROCK-myosin II axis induced the calcium transients. These data suggest universal coordination of RhoA and calcium signaling in cellular processes, such as cellular contraction and gene expression.
    Keywords:  NFAT transcription factor; Phospholipase C; Ras protein; Rho (Rho GTPase); calcium; inositol 1,4,5-triphosphate (IP3); optogenetics; signal transduction
  14. Cells. 2021 Jan 15. pii: E166. [Epub ahead of print]10(1):
      The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). Among numerous ECM components and modifiers that play a role in the physiological and pathological synaptic plasticity, matrix metalloproteinase 9 (MMP-9) has recently emerged as a key molecule. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Notably, MMP-9 signaling was shown to be indispensable for long-term memory formation that requires synaptic remodeling. The core regulators of the dynamic reorganization of the actin cytoskeleton and cell adhesion are the Rho family of GTPases. These proteins have been implicated in the control of a wide range of cellular processes occurring in brain physiology and pathology. Here, we discuss the contribution of Rho GTPases to MMP-9-dependent signaling pathways in the brain. We also describe how the regulation of Rho GTPases by post-translational modifications (PTMs) can influence these processes.
    Keywords:  MMP-9; extracellular matrix; post-translational modifications; small Rho GTPases; synaptic plasticity