Year: 2026
Type: preprint
Abstract: ABSTRACT 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 G q/11 -coupled P2Y receptors in renal interstitial fibroblasts and their involvement in experimental kidney fibrosis. Using highly selective RNA in situ hybridization, we detected P2Y 1 ( P2ry1 ) and P2Y 6 ( P2ry6 ) receptor expression in interstitial fibroblasts. Notably, P2Y 6 expression was markedly upregulated in several experimental mouse models of renal fibrosis. Functional assays in primary cultured renal fibroblasts confirmed G q/11 -coupled P2Y receptor activity, as evidenced by transient intracellular Ca 2+ elevations upon nucleotide stimulation. Primary cultured renal fibroblasts exhibited enhanced migration in response to extracellular uridine diphosphate (UDP). To assess the contribution of interstitial P2Y 6 receptors to fibrosis progression, we employed an adenine-induced nephropathy model with or without the selective P2Y 6 antagonist MRS2578. Pharmacological inhibition of P2Y 6 significantly reduced the mRNA expression of the myofibroblast marker α-smooth muscle actin and collagen I. Collectively, these findings suggest that upregulated P2Y 6 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 STATEMENT This study reveals the role of the P2Y 6 receptor ( P2ry6 ) in fibrotic processes in the kidney. P2Y 6 , a G q/11 protein-coupled UDP-sensitive receptor, is expressed in renal interstitial PDGFR-β-positive cells and macrophages. Its pharmacological inhibition significantly reduces fibrosis in the mouse adenine nephropathy model. Blocking P2Y 6 therefore represents a promising therapeutic strategy for kidney diseases characterized by excessive scarring.
Institution: University of Regensburg
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: green
Awards: Harvard Chronic Kidney Disease Research Biopsy Center, Multidimensional cellular interrogation of the kidney in AKI and CKD, Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury (PReCISE AKI), Kidney Precision Medicine Program (KPMP): Columbia AKI Recruitment Site, Spatial Elucidation of Human Acute Kidney Injury and Chronic Kidney Disease using Imaging Mass Cytometry, PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE), Minnesota Precision Medicine CKD & Resilient Diabetes Recruiting Site: Engagement, Enrollment & Ethics, Integrated spatial interrogation of cellular and molecular signatures of human kidney disease, Single cell multiomic and spatial atlas of acute and chronic kidney injury, Mount Sinai Health System Kidney Precision Medicine Project, University of Illinois at Chicago KPMP CKD Recruitment Site, AKI Matched Phenotype Linked Evaluation with Tissue (AMPLE-Tissue), Central Hub for Kidney Precision Medicine, Multimodal Imaging Mass Spectrometry and Spatial Omics for the Human Kidney, Boston Chronic Kidney Disease Research Biopsy Center, Cleveland Precision Medicine Chronic Kidney Disease Cohort, Kidney Precision Medicine Project - Patient Engagement, KPMP Kidney Mapping and Atlas Project (KMAP), Geographic and Environmental Health Equity in Kidney Precision Medicine, Spatial Multi-Omics to Profile Metabolic Pathways for Kidney Disease, Spatial Mapping of Proteomic and Transcriptional Signatures in Kidney Disease
OpenAlex ID: W7126041378