Inhibition of (interstitial) P2Y₆ receptors attenuates 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 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 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 G_q/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 α-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.