Mineralocorticoid Receptor-TRPC5 Axis Drives Macrophage-Mediated Inflammation in Diabetic Kidney Disease

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Although DKD is characterized by a low-renin state that limits aldosterone-driven mineralocorticoid receptor (MR) activation, aldosterone-independent MR activation occurs under conditions like diabetes and obesity, contributing to renal damage. Recent trials (FIGARO-DKD and FIDELIO-DKD) have shown that the non-steroidal MR antagonist finerenone provides renoprotection, supporting its use in DKD. However, the anti-inflammatory mechanisms remain unclear. Our previous studies showed that MR activation promotes inflammasome activity in macrophages. TRPC channels, particularly TRPC5, may regulate Ca2+ influx and modulate inflammatory responses. This study investigates the MR–TRPC pathway's role in inflammasome activation using a progressive DKD mouse model (eNOS-db/db). Methods: All mice had a C57BL/6 background. eNOS-KO db/db mice were generated by crossing eNOS-KO with type 2 diabetic db/db mice. Mice were randomized into three groups: WT, eNOS-KO db/db + vehicle, and eNOS-KO db/db + finerenone. Finerenone was administered from 8 to 12 weeks of age. All mice were sacrificed at 12 weeks. Macrophage infiltration was assessed by F4/80 immunofluorescence and qPCR. Fibrosis was evaluated using Masson's trichrome, collagen IV staining, and qPCR for fibrotic markers (TGFβ, CTGF, fibronectin). To investigate the relationship between MR activation and macrophage-mediated inflammation, we conducted in vitro assays using bone marrow–derived macrophages (BMDMs). Results: Finerenone significantly reduced albuminuria in eNOS-db/db mice versus vehicle controls. F4/80 staining showed increased macrophage infiltration in eNOS-db/db kidneys, which was attenuated by finerenone. In vitro, finerenone suppressed LPS-induced IL-6 expression in BMDMs cultured with aldosterone. Aldosterone upregulated TRPC5, and TRPC5 inhibition abolished IL-6 expression and Ca2+ influx. These findings indicate that the aldosterone–MR–TRPC5 axis drives macrophage inflammation, likely via NF-κB. Conclusion: Our study suggests that the MR–TRPC5 axis in macrophages as a key regulator of sustained inflammation in kidney disease.