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. 2025 Sep 15:377:123760.
doi: 10.1016/j.lfs.2025.123760. Epub 2025 May 24.

The axis of miR-30a/AIF-1/TRPC6/calcineurin A/NFAT2 regulated the death modalities and inflammation of renal tubular epithelial cells in diabetic kidney disease via exosome

Jianbing Hao  1 , Siyu Wang  2 , Xiaojun Guo  2 , Xinyu Guo  2 , Lirong Hao  3
Affiliations

The axis of miR-30a/AIF-1/TRPC6/calcineurin A/NFAT2 regulated the death modalities and inflammation of renal tubular epithelial cells in diabetic kidney disease via exosome

Jianbing Hao et al. Life Sci. .

Abstract

Aims: Diabetic kidney disease (DKD) is a significant complication of diabetes, marked by inflammation, fibrosis, and cell death in renal tissues. This study aimed to elucidate the regulatory role of miR-30a in DKD, focusing on its impact on monocyte/macrophage activity, key protein expression, exosomes, and renal cell death modalities.

Materials and methods: Using db/db mice as a DKD model, miR-30a expression was manipulated through knockout and overexpression techniques. Macrophage activity was evaluated via F4/80 expression and the M1/M2 macrophage ratio. Key proteins (AIF-1, TRPC6, calcineurin A, NFAT2, and NLRP3) were measured in renal tissues and exosomes from blood and urine. In vitro, TCMK-1 cells under high-glucose conditions were used to assess cell death modalities, including autophagy, apoptosis, pyroptosis, and necrosis.

Key findings: miR-30a inhibited macrophage activity, with increased F4/80 expression in knockout groups and decreased levels in overexpression groups. The M1/M2 macrophage ratio rose in knockout groups and fell in overexpression groups. miR-30a overexpression reduced key protein levels and urinary albumin (ALB), indicating a protective effect against DKD. Exosome concentration and protein content decreased in miR-30a-overexpressing mice. In vitro findings supported these results, highlighting miR-30a's regulatory effects on AIF-1, Caspase 3, TRPC6, Calcineurin A, NFAT2, and cell death modalities. Exosome secretion from TCMK-1 or RAW264.7 cells was affected by high-glucose conditions, influencing cell death modalities and functions of TCMK-1 cells.

Significance: The axis of miR-30a/AIF-1/TRPC6/calcineurin A/NFAT2 regulated death modalities and inflammation of renal tubular epithelial cells in DKD via exosome. miR-30a might be a novel therapeutic target to slow DKD.

Keywords: Cell death; Diabetic kidney disease; Exosome; Inflammation; microRNA-30a.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lirong Hao, Jianbing Hao reports financial support was provided by Shenzhen Science and Technology Program. Lirong Hao, Jianbing Hao reports financial support was provided by Sanming Project of Medicine in Shenzhen Nanshan. Lirong Hao, Jianbing Hao reports financial support was provided by Key Project of Subitem Funding for Technology Research and Creative Design in Nanshan District. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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