ArticleJournal of translational medicine2026
Cyclosporine A promotes renal fibrosis through activating endoplasmic reticulum stress by targeting miR-212-5p/ATF6 axis.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionCyclosporine A (CsA) is a widely used immunosuppressive drug, but its long-term use is associated with renal fibrosis. Despite its clinical importance, the molecular mechanisms underlying CsA-induced renal fibrosis remain poorly understood.
methodsWe used C57BL/6 mice (n = 6 per group) treated with CsA (30 mg/kg/day, gavage) and Boston University mouse proximal tubular (BUMPT) cells (n = 6 per group) exposed to CsA (8 µM). Assessments included Masson's trichrome staining, Western blot, quantitative real-time PCR, immunohistochemistry, and in situ hybridization. Mechanistic studies employed miR-212-5p mimics and inhibitors, activating transcription factor 6 (ATF6) overexpression, and the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid (4-PBA). Data are presented as mean ± standard deviation; statistical significance was defined as p < 0.05.
resultsCsA induced significant renal fibrosis in vivo and in vitro, evidenced by increased collagen deposition and elevated expression of alpha-smooth muscle actin (α-SMA), fibronectin, collagen type I and IV, and key profibrotic factors (p < 0.05). RNA analysis revealed that miR-212-5p was markedly upregulated in CsA-treated kidneys, predominantly in renal tubules. Concurrently, ATF6, a protective component of the unfolded protein response (UPR), was significantly downregulated. Bioinformatics prediction and luciferase reporter assays confirmed that miR-212-5p directly targets the 3' untranslated region of Atf6 mRNA. Functionally, miR-212-5p mimic exacerbated CsA-induced ATF6 suppression and fibrosis, whereas anti-miR-212-5p restored ATF6 expression, attenuated ER stress, and significantly reduced fibrotic markers. Similarly, ATF6 overexpression or ER stress inhibition with 4-PBA ameliorated CsA-induced fibrosis.
conclusionsOur findings position miR-212-5p as a previously unrecognized molecular target of CsA and establish the miR-212-5p/ATF6 axis as a central driver of CsA-induced nephrotoxicity. The findings provide new insights into the molecular mechanisms of CsA nephrotoxicity and identify a potential therapeutic target for preventing CsA-induced renal fibrosis.
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