Biology subjects

Warth, R.

Publications and source records attributed to Warth, R..

3 recordsLinked to original sources

bioRxiv2026

Inhibition of (interstitial) P2Y6 receptors attenuates renal fibrosis progression

Chronic kidney disease (CKD) affects over 850 million people worldwide and is characterized by progressive renal fibrosis driven by activated interstitial fibroblasts. Signaling by extracellular nucleotides and P2 receptors plays an important role in renal pathophysiology, yet its contribution to fibroblast activation and fibrosis remains poorly understood. Here, we investigated the expression and function of Gq/11-coupled P2Y receptors in renal interstitial fibroblasts and their involvement in experimental kidney fibrosis. Using highly selective RNA in situ hybridization, we detected P2Y1 (P2ry1) and P2Y6 (P2ry6) receptor expression in interstitial fibroblasts. Notably, P2Y6 expression was markedly upregulated in several experimental mouse models of renal fibrosis. Functional assays in primary cultured renal fibroblasts confirmed Gq/11-coupled P2Y receptor activity, as evidenced by transient intracellular Ca2+ elevations upon nucleotide stimulation. Primary cultured renal fibroblasts exhibited enhanced migration in response to extracellular uridine diphosphate (UDP). To assess the contribution of interstitial P2Y6 receptors to fibrosis progression, we employed an adenine-induced nephropathy model with or without the selective P2Y6 antagonist MRS2578. Pharmacological inhibition of P2Y6 significantly reduced the mRNA expression of the myofibroblast marker -smooth muscle actin and collagen I. Collectively, these findings suggest that upregulated P2Y6 receptor signaling promotes the transition of resident interstitial cells into myofibroblasts during renal fibrosis, likely by modulating fibroblast migration. Inhibition of P2Y6 signaling could represent a new strategy for reducing excessive renal fibrosis. TRANSLATIONAL STATEMENTThis study reveals the role of the P2Y6 receptor (P2ry6) in fibrotic processes in the kidney. P2Y6, a Gq/11 protein-coupled UDP-sensitive receptor, is expressed in renal interstitial PDGFR-{beta}-positive cells and macrophages. Its pharmacological inhibition significantly reduces fibrosis in the mouse adenine nephropathy model. Blocking P2Y6 therefore represents a promising therapeutic strategy for kidney diseases characterized by excessive scarring.

physiology↗

bioRxiv2024

Somatic Mutations in MCOLN3 in Aldosterone-Producing Adenomas cause Primary Aldosteronism.

Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase (CYP11B2) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of CYP11B2 transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increased CYP11B2 expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in MCOLN3 which encodes for mucolipin-3 (TRPML3) -- a highly conserved inwardly-rectifying, cation-permeable channel. These MCOLN3 mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing MCOLN3 mutations in humans. Functional studies suggest MCOLN3Y391D might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased CYP11B2 transcription and aldosterone production. This study implicates mutated MCOLN3 as a driver of aldosterone excess in primary aldosteronism. Significance StatementPrimary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in human MCOLN3 in aldosterone-producing adenomas (APAs) devoid of known mutations. In vitro investigations showed the MCOLN3 variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.

genetics↗

bioRxiv2022

Zinc transporter somatic gene mutations cause primary aldosteronism

Primary aldosteronism (PA) is the most common form of endocrine hypertension and effects one in 50 adults. PA is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants are situated in close proximity of the zincbinding site (H43 and D47) in transmembrane domain II and likely cause abnormal ion transport. PA cases with the unique SLC30A1 mutations showed male dominance and demonstrated increased aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A151_57del variant in a doxycycline-inducible adrenal cell system revealed abnormal Na+ conductivity caused by the mutant, which in turn led to the depolarization of the resting membrane potential, and thus to the opening of voltage-gated calcium channels. This resulted in an increase in cytosolic Ca2+ activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA.

genetics↗