MicroRNA-10a/b inhibit TGF-β/Smad-induced renal fibrosis by targeting TGF-β receptor 1 in diabetic kidney disease

• Published in: Molecular therapy. Nucleic acids Vol. 28; pp. 488 - 499
• Main Authors: Li, Jinxiang, Yue, Shuling, Fang, Jingwen, Zeng, Junling, Chen, Siqi, Tian, Jianwei, Nie, Sheng, Liu, Xiaoting, Ding, Hanying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-06-2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: diabetic kidney disease; MicroRNA-10a/b; MT: Non-coding RNAs; Original; renal fibrosis; TGF-β receptor 1; TGF-β/Smad signaling; diabetic kidney disease; MT: Non-coding RNAs; renal fibrosis; TGF-β receptor 1; TGF-β/Smad signaling; MicroRNA-10a/b
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.04.002

TGF-β/Smad signaling plays a vital role in the development of fibrosis in diabetic kidney disease (DKD). However, remedies targeting key elements in TGF-β/Smad signaling are lacking. Here, we found that TGF-β receptor 1 (TGFBR1), a key protein in TGF-β/Smad signaling, was upregulated in kidney from diabetic mice and patients with DKD. Induction of TGFBR1 was regulated by microRNA-10a and -10b (miR-10a/b) by a post-transcriptional mechanism. Furthermore, the decreased XRN2, an exoribonuclease, was identified to contribute to affecting miR-10a/b maturation in vitro. In streptozotocin (STZ)-induced DKD mice, preventing the reduction of miR-10a/b in the kidney by an in situ lentivirus-injection method attenuated collagen deposition and foot process effacement, whereas deprivation of miR-10a/b aggravated renal fibrosis. Mechanistically, manipulating miR-10a/b in the kidney influenced TGFBR1 protein expression, TGF-β/Smad signaling activation, and downstream pro-fibrotic genes expression including fibronectin (FN) and α-smooth muscle actin (α-SMA). In a cohort of patients diagnosed DKD, renal miR-10a/b expressions were downregulated, whereas both TGFBR1 and fibrosis were enhanced. Our finding suggests that overexpressing miR-10a/b in kidney may be a promising method for the treatment of fibrosis in DKD.
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TGF-β/Smad signaling plays a vital role in the development of fibrosis in diabetic kidney disease. This study found that microRNA-10 inhibits fibrosis by suppressing TGF-β receptor 1, the key protein in TGF-β/Smad signaling, suggesting that targeting TGF-β receptor 1 by microRNA-10 is a promising method for treatment of diabetic kidney disease.