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

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.

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

Circulation ◽

10.1161/circ.132.suppl_3.17562 ◽

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.

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

10.1101/2021.09.27.21263789 ◽

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.

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Potential to Target Circulating miRNAs, Indicative of Renal Fibrosis, in Canines with Chronic Kidney Disease Through Dietary Intervention

Current Developments in Nutrition ◽

10.1093/cdn/nzaa068_024 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1539-1539

Author(s):

Selena Tavener ◽

Kiran Panickar

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Dietary Intervention ◽

Kidney Injury ◽

Experimental Models ◽

Circulating Mirnas ◽

Down Regulation ◽

Renal Fibrogenesis

Abstract Objectives Mature microRNAs (miRNAs) are single-stranded RNAs approximately 22 nucleotides in length that act as posttranscriptional regulators by base-pairing with complementary sequences to mRNAs, leading to the silencing of mRNA. Circulating miRNAs may also serve as biomarkers for renal dysfunction including renal fibrosis which results in a progressive loss of renal function. We assessed circulating levels of miRNAs in the blood of dogs that were clinically diagnosed as having chronic kidney disease (CKD), post-mortem. Methods We used Qiagen's Canine mScript miRNA PCR array from blood samples that were collected at necropsy from dogs with CKD (n = 10; 2–17 yr) and control dogs (n = 10; 5–13.5 yr). End-of-life pathology reports indicated interstitial inflammation, fibrosis, and thickening of the Bowman's capsule. Results There was a significant decline in the levels of miRNAs cfa-let-7a, let-7c, let-7f, and let-7g in dogs with CKD when compared to controls (P < 0.05). Down-regulation of certain let-7 miRNAs (let-7a, let-7b) has been associated with experimental models of induction of renal fibrogenesis. There was also a > 2-fold reduction (ns) in levels of cfa-miR-93, cfa-miR-122, cfa-miR-200a, and cfa-miR-204, in CKD when compared to controls. These microRNAs have been demonstrated to have anti-fibrogenesis effect, and are also down-regulated in rodent models and in vitro mechanistic models of renal fibrosis leading to increased fibrosis. There was also a down-regulation of cfa-miR-16, which is consistent with its reported role in attenuating kidney injury independent of fibrosis. Taken together with the literature, down-regulation of these miRNAs may be indicative of a reduction in their role in attenuating renal fibrogenesis and injury. Importantly, the circulating miRNAs may serve as non-invasive biomarkers for renal fibrosis in CKD and also as nutritional targets for slowing the progression of fibrosis in kidney disease. Conclusions Our data show evidence of renal fibrosis markers that could have contributed to a progressive decline in kidney function. Nutritional therapy to slow the progression of kidney dysfunction may benefit from dietary ingredients including polyphenols that have been shown to upregulate miRNAs. Funding Sources Funded by Hills PNC, Inc.

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

Scientific Reports ◽

10.1038/s41598-020-77952-9 ◽

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.

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

Human Molecular Genetics ◽

10.1093/hmg/ddab322 ◽

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.

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AIM2 Inflammasome Contributes to Aldosterone-induced Renal Injury via Endoplasmic Reticulum Stress

Clinical Science ◽

10.1042/cs20211075 ◽

2021 ◽

Author(s):

Yong Wu ◽

Huan Yang ◽

Sujuan Xu ◽

Ming Cheng ◽

Jie Gu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Endoplasmic Reticulum ◽

Kidney Disease ◽

Endoplasmic Reticulum Stress ◽

Renal Injury ◽

Renal Fibrosis ◽

Inflammasome Activation ◽

Mineralocorticoid Receptor Antagonist

Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental chronic kidney disease. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lower systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro while they failed to produce a more remarkable reno-protective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.

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Stroke in chronic renal failure

Orvosi Hetilap ◽

10.1556/oh.2008.28292 ◽

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.

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Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

Cell Death and Disease ◽

10.1038/s41419-021-03709-5 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Bohan Chen ◽

Pei Wang ◽

Xianhui Liang ◽

Chunming Jiang ◽

Yan Ge ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Binding Protein ◽

Renal Tubules ◽

Genetic Ablation ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Renal Fibrogenesis ◽

Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

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