Journal of the American Society of Nephrology : JASN

BACKGROUND: Thiazide diuretics are associated with glucose intolerance and new onset diabetes mellitus. Previous studies demonstrated that thiazides attenuate insulin secretion, but the molecular mechanisms remain elusive. We hypothesized that thiazides attenuate insulin secretion via one of the known molecular thiazide targets in β-cells. METHODS: We performed static insulin secretion experiments with islets of wild-type, NCC (SLC12A3), and NDCBE (SLC4A8) knock-out (KO) mice and with murine Min6 cells with individual knock-down of carbonic anhydrase (CA) isoforms to identify the molecular target of thiazides in β-cells...

BACKGROUND: The highly conserved Hippo pathway, which regulates organ growth and cell proliferation by inhibiting transcriptional co-factors YAP/TAZ, plays a special role in podocytes, where activation of the pathway leads to apoptosis. The Ajuba family proteins (Ajuba, LIMD1 and WTIP) can bind and inactivate LATS1/2, two of the Hippo pathway key kinases. WTIP furthermore connects the slit diaphragm (SD), the specialized cell-cell junction between podocytes, with the actin cytoskeleton...

BACKGROUND: Change in log urinary albumin to creatinine ratio (UACR) and GFR slope are individually used as surrogate endpoints in clinical trials of CKD progression. Whether combining these surrogate endpoints might strengthen inferences about clinical benefit is unknown. METHODS: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical endpoint (sustained doubling of serum creatinine, GFR<15 ml/min per 1...

BACKGROUND: Of the consequences of kidney failure in childhood, those rated as most important by children and their caregivers are its effects on long-term survival. From a life-course perspective, little is known about the experience of kidney failure treatment or long-term survival. METHODS: To determine expected years of life lost and treatment trajectory for kidney failure in childhood, we conducted a population-based cohort study of all children aged ≤18 years with treated kidney failure in Australia (1980 to 2019) and New Zealand (1988 to 2019)...

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No abstract text is available yet for this article.

BACKGROUND: Crescentic glomerulonephritis (cGN) is an aggressive form of immune-mediated kidney disease that is an important cause of end-stage renal failure. Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a common cause. T cells infiltrate the kidney in cGN, but their precise role in autoimmunity is not known. METHODS: Combined single-cell RNA sequencing and single-cell T cell receptor sequencing were conducted on CD3+ T cells isolated from renal biopsies and blood of patients with ANCA-associated cGN and from kidneys of mice with experimental cGN...

BACKGROUND: Increasing evidence implicates the signaling kinase mTOR complex-2 (mTORC2) in rapid renal responses to changes in plasma potassium concentration [K+]. However, the underlying cellular and molecular mechanisms that are relevant in vivo for these responses remain controversial. METHODS: We used Cre-Lox-mediated knockout of rapamycin-insensitive companion of TOR (Rictor) to inactivate mTORC2 in kidney tubule cells of mice. In a series of time-course experiments in wild-type and knockout mice, we assessed urinary and blood parameters and renal expression and activity of signaling molecules and transport proteins following a K+ load via gavage...

BACKGROUND: Hemodialysis treatment-related hemodynamic stress results in recurrent ischemic injury to organs such as the heart and brain. Short-term reduction in brain blood flow and long-term white matter changes have been reported, but the basis of hemodialysis-induced brain injury is neither well-recognized nor understood, even though progressive cognitive impairment is common. METHODS: We used neurocognitive assessments, intradialytic anatomical magnetic resonance imaging (MRI), diffusion tensor imaging, and proton magnetic resonance spectroscopy (1H-MRS) to examine the nature of acute hemodialysis-associated brain injury and associated changes in brain structure and neurochemistry relevant to ischemia...

BACKGROUND: Cardiovascular diseases are the leading cause of mortality in kidney transplant (KT) recipients, accounting for 32% of deaths. Statins are widely used in KT recipients, but effectiveness for preventing mortality remains unclear in this population, especially because of interaction between statins and immunosuppressive agents. We analyzed a national cohort to assess the real-world effectiveness of statins for reducing all-cause mortality in KT recipients. METHODS: We studied statin use and mortality among 58,264 adults (≥18y) who received single kidneys between 2006 and 2016 and had Medicare Part A/B/D...

BACKGROUND: Proteomic techniques have facilitated understanding of pathways that mediate decline in GFR. Albuminuria is a key component of chronic kidney disease (CKD) diagnosis, staging, and prognosis, but has been less studied than GFR. We sought to investigate circulating proteins associated with higher albuminuria. METHODS: We evaluated the cross-sectional associations of the blood proteome with albuminuria and longitudinally with doubling of albuminuria in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; mean GFR 46; median urine protein-to-creatinine ratio [PCR] 81 mg/g; n = 703) and replicated in two external cohorts: a subset of the Atherosclerosis Risk in Communities (ARIC) study with chronic kidney disease and the Chronic Renal Insufficiency Cohort (CRIC)...

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Podocytes and parietal epithelial cells (PECs) are among the few principal cell types within the kidney glomerulus, the former serving as a crucial constituent of the kidney filtration barrier and the latter representing a supporting epithelial layer that adorns the inner wall of Bowman's capsule. Podocytes and PECs share a circumscript developmental lineage that only begins to diverge during the S-shaped body stage of nephron formation - occurring immediately before the emergence of the fully mature nephron...

BACKGROUND: Ischemic acute kidney injury (IR-AKI) is estimated to affect 2-7% of all hospitalized patients. The significant morbidity and mortality associated with AKI indicates urgent need for effective treatments. Prior studies have shown activation of the vascular Angiopoietin-Tie2 tyrosine kinase signaling pathway abrogates IRI. We extended prior studies to 1) determine the molecular mechanism(s) underlying kidney injury and protection related to decreased or increased activation of Tie2, respectively, and 2) to test the hypothesis that deletion of the Tie2 inhibitory phosphatase VE-PTP or injection of a new Angiopoietin mimetic protects the kidney from IRI by common molecular mechanism(s)...

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BACKGROUND: Loss of function of the 2Cl-/H+ antiporter ClC-5 in Dent disease impairs the uptake of filtered proteins by the kidney proximal tubule, resulting in tubular proteinuria. Reduced posttranslational stability of megalin and cubilin, the receptors that bind to and recover filtered proteins, is believed to underlie the tubular defect. How loss of ClC-5 leads to reduced receptor expression remains unknown. METHODS: We used biochemical and quantitative imaging data to adapt a mathematical model of megalin traffic in ClC-5 knockout and control cells...

BACKGROUND: Clinical practice lacks strategies to treat acute kidney injury (AKI). Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. METHODS: CRISPR generated kynureninase (KYNU) knockout mice and comparative transcriptome, proteome, and metabolite analyses of murine kidneys (C57Bl6N wild type and KYNU-deficient) pre- and post-ischemia-reperfusion injury, in the context of CR or ad libitum diet, performed...

BACKGROUND: Ureteric bud induction and branching morphogenesis is fundamental to the establishment of the renal architecture and is a key determinant of nephron number. Defective ureteric bud morphogenesis could give rise to a spectrum of malformations associated with congenital anomalies of the kidney and urinary tract (CAKUT). Signaling involving glial cell line-derived neurotrophic factor and its receptor RET and coreceptor GFRA1 appears to be particularly important in ureteric bud development...

BACKGROUND: Sex differences have been increasingly recognized as important in kidney physiology and pathophysiology, but limited resources are available for comprehensive interrogation of sex differences. METHODS: RNA-seq and ATAC-seq of microdissected mouse proximal tubules and protein mass spectrometry of homogenized perfused mouse kidneys reveal differences in proximal tubule cells of males and females. RESULTS: The transcriptomic data indicated that the major differences in the proximal tubules between the sexes were in the S2/S3 segments and the majority of the sex-biased transcripts mapped to autosomes rather than to the sex chromosomes...

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