The Mineralocorticoid Receptor–TRPC5 pathway Drives Macrophage-Mediated Inflammation in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease (ESRD). In DKD, a low-renin state typically limits aldosterone-dependent activation of the mineralocorticoid receptor (MR). However, under pathological conditions such as diabetes and obesity, aldosterone-independent MR activation occurs and contributes to renal injury progression. Recent clinical trials (FIGARO-DKD and FIDELIO-DKD) have demonstrated the renoprotective effects of finerenone, a non-steroidal MR antagonist, prompting its use in DKD treatment. Nevertheless, the underlying anti-inflammatory mechanisms remain incompletely understood. Our previous studies indicated that MR activation enhances inflammasome activity in macrophages, thereby promoting inflammation. In particular, transient receptor potential canonical (TRPC) channels may regulate calcium (Ca²⁺) influx, acting as crucial modulators of macrophage inflammatory responses. This study aimed to elucidate the role of the MR–TRPC pathway in inflammasome activation using a progressive DKD mouse model (eNOS-KO db/db).

All mice background is C57BL/6. eNOS-KO db/db mice were generated by crossing endothelial nitric oxide synthase knockout (eNOS-KO) mice with type 2 diabetic db/db mice. We randomized into three groups, WT, eNOS-KO db/db with vehicle and eNOS-KO db/db with Finerenone. eNOS-KO db/db were treated with Finerenone for 4weeks from 8 weeks of age in eNOS-KO db/db with Finerenone group. All mice sacrificed at 12 weeks of age. Macrophage infiltration was examined via F4/80 immunofluorescence staining and qPCR. Fibrosis was evaluated by Masson's trichrome staining, collagen IV staining, and qPCR analysis of fibrosis-related genes (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). 

Administration of finerenone significantly reduced albuminuria in eNOS-KO db/db mice compared to the eNOS-KO db/db vehicle-treated group. Increased infiltration of macrophages, as detected by F4/80 immunostaining, was observed in the kidneys of eNOS-KO db/db mice relative to control mice. Finerenone treatment markedly attenuated this macrophage infiltration. In BMDMs cultured in aldosterone-containing media, finerenone suppressed LPS-induced secretion of IL-6 to supernatant. Aldosterone stimulation led to an upregulation of TRPC5 protein expression in BMDMs. Notably, inhibition of TRPC5, but not TRPC6, completely abolished LPS-induced IL-6 expression and secretion. Furthermore, LPS stimulation triggered a calcium (Ca²⁺) influx in BMDMs, which was effectively suppressed by TRPC5 inhibition. These findings suggest that the aldosterone–MR–TRPC5 signaling pathway contributes to inflammatory responses in macrophages, potentially via the NF-κB pathway.

Our study suggests that the renal protective effects of finerenone are at least partly mediated by suppression of chronic inflammation. We revealed that the MR–TRPC5 pathway in macrophage has a pivotal role of maitainof chronic inflammation in kidney diseases.