Finerenone Regulates Macrophage-Tubular Crosstalk in Diabetic Nephropathy via the AMPK/PKM2 Pathway

To clarify how finerenone (FIN) regulates macrophage-renal tubular crosstalk in diabetic nephropathy (DN) via the AMPK/PKM2 pathway.

Diabetes was experimentally induced in C57BL/6J mice via intraperitoneal injection of streptozotocin after high-fat diet feeding for eight weeks. FIN treatment was initiated five days after diabetes induction and continued for 12 weeks. DN in mice was evaluated by measuring blood glucose, urea nitrogen, creatinine, and urinary microalbumin, together with histopathological evaluation. Mouse BMDMs were exposed to high glucose (HG) and treated with FIN and the AMPK inhibitor compound C (CC). Polarization of BMDMs was assessed by immunofluorescence and western blot. A co-culture system was established by treating mouse renal tubular epithelial cells (RTECs) with conditioned medium (CM) from BMDMs. The viability of mouse RTECs, the expression levels of NGAL and KIM-1, and apoptosis-related proteins in mouse RTECs were measured.

FIN alleviated renal injury in mice with DN. Experimental evidence indicated that FIN inhibited macrophage M1 polarization and promoted AMPK/PKM2 pathway activation. In HG-stimulated FIN-treated BMDMs, CC significantly suppressed the activity of the AMPK/PKM2 pathway and promoted M1 polarization of BMDMs. In the co-culture system, the CM from HG-treated BMDMs inhibited mouse RTECs viability, increased the expression of KIM-1 and NGAL proteins, and induced apoptosis. In contrast, the CM from HG- and FIN-treated BMDMs enhanced mouse RTECs viability, reduced the expression of KIM-1 and NGAL proteins, and suppressed apoptosis.

FIN ameliorates DN by regulating the AMPK/PKM2 pathway to influence macrophage polarization and attenuate RTEC injury.