scholarly journals An intermediate effect size variant in UMOD confers risk for chronic kidney disease

2021 ◽  
Author(s):  
Eric Olinger ◽  
Celine Schaeffer ◽  
Kendrah Kidd ◽  
Yurong Cheng ◽  
Ines Dufour ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Diseases ◽  
Large Population ◽  
Genetic Load ◽  
European Ancestry ◽  
Specific Gene ◽  
Incomplete Penetrance ◽  
Intermediate Effect

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare, large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD) while common, low-effect variants strongly associate with kidney function and risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in gnomAD with MAF ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD and is associated with kidney failure in the 100,000 Genomes Project (OR 3.99; 1.84-8.98) and the UK Biobank (OR 4.12; 1.32-12.85). Compared to canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD, intermediate reduction of urinary UMOD levels, in line with an intermediate trafficking defect in vitro. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides novel insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Abstract 17562: GPCR Gβγ Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Fadia A Kamal ◽  
Joshua G Travers ◽  
Allison E Schafer ◽  
Qing Ma ◽  
Prasad Devarajan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
G Protein ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Direct Role

Background: Cardiorenal syndrome type 2 (CRS2), the development of chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is clinically associated with increased incidence of organ failure and reduced survival. Heart and kidney damage in CRS2 is greatly caused by chronic stimulation of the adrenergic and endothelin receptors as a result of elevated neurohormonal signaling of the sympathetic nervous system (SNS) and its downstream endothelin (ET) system, respectively. These receptors belong to the superfamily of G protein-coupled receptors (GPCRs). While chronic GPCR stimulation and its associated upregulated interaction between the G-protein βγ subunit (Gβγ), the GPCR-kinase 2 (GRK2) and β-arrestin are known to be central to various cardiovascular diseases, their role in kidney diseases are by far unknown and beg investigation. Objective: CRS2 animal studies utilize combine ischemic cardiac injury and renal injury, which is of poor clinical relevance. Our study investigates: (1) the development of chronic kidney disease (CKD) in a model of non-ischemic CHF without inducing surgical kidney injury, aiming to establish a more clinically relevant CRS2 model. (2) The possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in the established CRS2 model. Methods and results: We utilized transverse aortic constriction (TAC) as a non-ischemic hypertrophic murine CHF model. Twelve weeks after TAC, mice developed CKD secondary to CHF suggesting a CRS2 model. This was associated with elevated renal GPCR-Gβγ signaling and ET system expression. Importantly, systemic pharmacologic Gβγ inhibition by gallein attenuated these renal pathological changes in parallel with alleviated CHF. A direct effect of gallein on the kidney was subsequently confirmed in a bilateral ischemia reperfusion acute kidney injury (AKI) mouse model where it attenuated renal dysfunction, tissue damage and ET system activation, indicating a direct role for GPCR-Gβγ signaling in AKI. Further, in vitro studies in mouse embryonic fibroblasts showed a key role for ET receptor-Gβγ signaling in fibroblast activation. Conclusion: Our data suggest TAC as a clinically relevant CRS2 model and GPCR-Gβγ inhibition as a novel therapeutic approach for CRS2 and AKI.

scholarly journals SHROOM3, the gene associated with chronic kidney disease, affects the podocyte structure

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ryo Matsuura ◽  
Atsuko Hiraishi ◽  
Lawrence B. Holzman ◽  
Hiroki Hanayama ◽  
Koji Harano ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Genome Wide Association Study ◽  
Kidney Diseases ◽  
Vitro Experiment ◽  
Public Health Burden ◽  
In Vitro Experiment

AbstractChronic kidney disease is a public health burden and it remains unknown which genetic loci are associated with kidney function in the Japanese population, our genome-wide association study using the Biobank Japan dataset (excluding secondary kidney diseases, such as diabetes mellitus) clearly revealed that almost half of the top 50 single nucleotide polymorphisms associated with estimated glomerular filtration rate are located in the SHROOM3 gene, suggesting that SHROOM3 will be responsible for kidney function. Thus, to confirm this finding, supportive functional analyses were performed on Shroom3 in mice using fullerene-based siRNA delivery, which demonstrated that Shroom3 knockdown led to albuminuria and podocyte foot process effacement. The in vitro experiment shows that knockdown of Shroom3 caused defective formation of lamellipodia in podocyte, which would lead to the disruption of slit diaphragm. These results from the GWAS, in vivo and in vitro experiment were consistent with recent studies reporting that albuminuria leads to impairment of kidney function.

Biallelic ANKS6 mutations cause late onset ciliopathy with chronic kidney disease through YAP dysregulation

2021 ◽  
Author(s):  
Hannah Schwarz ◽  
Bernt Popp ◽  
Rannar Airik ◽  
Nasrin Torabi ◽  
Karl X Knaup ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Primary Cilia ◽  
Target Genes ◽  
Late Onset ◽  
Kidney Diseases ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Altered Expression

Abstract Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represent the one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remains unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late onset chronic kidney disease by whole exome sequencing. We employed patient derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient derived cells showed an impaired integrity of the ciliary Inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear YAP imbalance, and disrupted ciliary localization of YAP. Additionally an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) β-catenin and phosphorylated GSK3β were observed. Upon ciliation ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.

scholarly journals Effects of HIF-1α on renal fibrosis in cisplatin-induced chronic kidney disease

2021 ◽  
Author(s):  
Hao Zhao ◽  
Yu Liu ◽  
Yachun Han ◽  
Na Jiang ◽  
Chenrui Li ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Gene Knockout ◽  
Notch 1 ◽  
Primary Mouse ◽  
Proximal Tubular ◽  
In Cis

Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and posttranscriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.

Stroke in chronic renal failure

2008 ◽  
Vol 149 (15) ◽  
pp. 691-696
Author(s):  
Dániel Bereczki
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Disease ◽  
Chronic Renal Disease ◽  
Kidney Diseases ◽  
Cerebrovascular Diseases ◽  
Lipid Lowering ◽  
Increased Risk ◽  
Intracerebral Hemorrhages

Chronic kidney diseases and cardiovascular diseases have several common risk factors like hypertension and diabetes. In chronic renal disease stroke risk is several times higher than in the average population. The combination of classical risk factors and those characteristic of chronic kidney disease might explain this increased risk. Among acute cerebrovascular diseases intracerebral hemorrhages are more frequent than in those with normal kidney function. The outcome of stroke is worse in chronic kidney disease. The treatment of stroke (thrombolysis, antiplatelet and anticoagulant treatment, statins, etc.) is an area of clinical research in this patient group. There are no reliable data on the application of thrombolysis in acute stroke in patients with chronic renal disease. Aspirin might be administered. Carefulness, individual considerations and lower doses might be appropriate when using other treatments. The condition of the kidney as well as other associated diseases should be considered during administration of antihypertensive and lipid lowering medications.

scholarly journals Soluble Fas affects erythropoiesis in vitro and acts as a potential predictor of erythropoiesis-stimulating agent therapy in patients with chronic kidney disease

2020 ◽  
Vol 318 (4) ◽  
pp. F861-F869
Author(s):  
Daniela Mendes Chiloff ◽  
Danilo Candido de Almeida ◽  
Maria A. Dalboni ◽  
Maria Eugênia Canziani ◽  
Sunil K. George ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Dependent Manner ◽  
Potential Predictor ◽  
Soluble Fas ◽  
Esa Therapy

Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels ( r = 0.30, P = 0.001) but negatively with hemoglobin ( r = −0.55, P < 0.001) and glomerular filtration rate ( r = −0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration ( r = −0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.

Nutritional compounds influence tissue factor expression and inflammation of chronic kidney disease patients in vitro

Nutrition ◽  
2011 ◽  
Vol 27 (9) ◽  
pp. 967-972 ◽  
Author(s):  
Cecilia M. Shing ◽  
Murray J. Adams ◽  
Robert G. Fassett ◽  
Jeff S. Coombes
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Tissue Factor ◽  
Tissue Factor Expression ◽  
Factor Expression ◽  
Nutritional Compounds

scholarly journals High prevalence of chronic kidney disease in Iran: a large population-based study

2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Farhad Hosseinpanah ◽  
Farshad Kasraei ◽  
Amir A Nassiri ◽  
Fereidoun Azizi
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Large Population ◽  
Population Based ◽  
Population Based Study ◽  
High Prevalence

scholarly journals GENETIC KIDNEY DISEASES AS AN UNDERECOGNIZED CAUSE OF CHRONIC KIDNEY DISEASE: THE KEY ROLE OF INTERNATIONAL REGISTRY REPORTS

2021 ◽  
Author(s):  
Roser Torra ◽  
Mónica Furlano ◽  
Alberto Ortiz ◽  
Elisabet Ars
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Diseases ◽  
Unknown Etiology ◽  
Correct Treatment ◽  
Monogenic Diseases ◽  
High Prevalence ◽  
Incorrect Diagnosis ◽  
Kidney Replacement Therapy

Abstract Inherited kidney diseases (IKDs) are among the leading causes of early-onset chronic kidney disease (CKD) and are responsible for at least 10–15% of cases of kidney replacement therapy (KRT) in adults. Pediatric nephrologists are very aware of the high prevalence of IKDs among their patients, but this is not the case for adult nephrologists. Recent publications have demonstrated that monogenic diseases account for a significant percentage of adult cases of CKD. A substantial number of these patients have received a non-specific/incorrect diagnosis or a diagnosis of CKD of unknown etiology, which precludes correct treatment, follow-up and genetic counseling. There are a number of reasons why genetic kidney diseases are difficult to diagnose in adulthood: a) adult nephrologists, in general, are not knowledgeable about IKDs, b) existence of atypical phenotypes, c) genetic testing is not universally available, d) family history is not always available or may be negative, e) lack of knowledge of various genotype–phenotype relationships, f) conflicting interpretation of the pathogenicity of many sequence variants.

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