Myocardin-related transcription factor A contributes to diabetic nephropathy by activating integrin β2 in macrophages

Diabetic nephropathy (DN) is one of the most severe complications for diabetic patients. Previously it has been reported that myocardin-related transcription factor A contributes to DN-associated renal fibrosis by regulating fibroblast phenotype. In the present study we investigated the contribution of macrophage derived MRTF-A to DN pathogenesis.

Macrophage conditional MRTF-A knockout (CKO) mice were generated by cross-breeding the Mrtfa^f/f mice to the LyzM-Cre mice. DN was modeled in mice by high-fat diet (HFD) feeding and streptozotocin (STZ) injection.

Compared to the wild type (WT) mice, the MRTF-A CKO mice developed a less severe phenotype of diabetic nephropathy as measured by plasma BUN levels, urinary albumin/creatinine levels, and renal pathohistology. On the contrary, mice harboring macrophage conditional MRTF-A over-expression (CKI) developed a more severe phenotype of diabetic nephropathy than the WT mice. Mechanistically, MRTF-A activated integrin β2 (Itgb2) transcription in macrophages exposed to high glucose treatment to promote endothelial adhesion. Consistently, integrin β2 blockade with a neutralizing antibody significantly ameliorated diabetic nephropathy in mice. Finally, a correlation between MRTF-A and integrin β2 was detected in macrophages in a mouse model of diabetic nephropathy by single-cell RNA-seq analysis.

Our data suggest that MRTF-A may play an important role in diabetic nephroatphy by activating Itgb2 transcription in macrophages.