Gallic Acid Alleviates Glucolipotoxicity-Induced Nephropathy by miR-709-NFE2L2 Pathway in db/db Mice on a High-Fat Diet.

BACKGROUND

Type 2 diabetes mellitus (T2DM) has become a major global issue, with diabetic nephropathy (DN) ranking as one of its most serious complications. The involvement of microRNAs (miRNAs) in the progression of T2DM and DN is an area of active research, yet the molecular mechanisms remain only partially elucidated. Gallic acid (GA), a naturally occurring polyphenolic compound found in various plants such as bearberry leaves, pomegranate root bark, tea leaves, and oak bark, has demonstrated antioxidant properties that may offer therapeutic benefits in DN.

METHODS AND RESULTS

The study aimed to investigate the therapeutic potential of GA in mitigating kidney fibrosis, oxidative stress and inflammation, within a glucolipotoxicity-induced diabetic model using db/db mice. The mice were subjected to a high-fat diet to induce glucolipotoxicity, a condition that mimics the metabolic stress experienced in T2DM. Through microarray data analysis, we identified a significant upregulation of renal miR-709a-5p in the diabetic mice, linking this miRNA to the pathological processes underlying DN. GA treatment was shown to boost the activity of including catalase, essential antioxidant enzymes, glutathione peroxidase and superoxide dismutase, while also reducing lipid accumulation in the kidneys, indicating a protective effect against HFD-induced steatosis. In vitro experiments further revealed that silencing miR-709a-5p in MES-13 renal cells led to a reduction in oxidative stress markers, notably lowering lipid peroxidation markers, and significantly boosting the activity of antioxidant defenses. Additionally, NFE2L2, a crucial transcription factor involved in the antioxidant response, was identified as a direct target of miR-709a-5p. The downregulation of miR-709a-5p by GA suggests that this polyphenol mitigates glucolipotoxicity-induced lipogenesis and oxidative stress, potentially offering a novel therapeutic avenue for managing diabetic fatty liver disease and DN.

CONCLUSION

Our findings indicate that GA exerts a protective effect in DN by downregulating miR-709a-5p, thereby alleviating oxidative stress through the suppression of NFE2L2. The results highlight the potential of GA and NFE2L2-activating agents as promising therapeutic strategies in the treatment of DN.