Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b
| Autor: | Hui Y. Lan, Ping Li, Min Feng, Xiao R. Huang, Si F. Sun, Ronald C.W. Ma, Patrick Ming-Kuen Tang, Jun Xiao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Kidney Endocrinology Diabetes and Metabolism Kidney metabolism SMAD Transforming growth factor beta Biology medicine.disease Diabetic nephropathy 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis microRNA Internal Medicine Renal fibrosis Cancer research medicine biology.protein Gene silencing |
| Zdroj: | Diabetes. 67:731-744 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db17-0816 |
| Popis: | Transforming growth factor-β/Smad signaling plays an important role in diabetic nephropathy. The current study identified a novel Smad3-dependent long noncoding RNA (lncRNA) Erbb4-IR in the development of type 2 diabetic nephropathy (T2DN) in db/db mice. We found that Erbb4-IR was highly expressed in T2DN of db/db mice and specifically induced by advanced glycosylation end products (AGEs) via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN, such as elevated microalbuminuria, serum creatinine, and progressive renal fibrosis in db/db mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR–microRNA (miR)-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3′ untranslated region of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR increased miR-29b and therefore protected the kidney from progressive renal injury in db/db mice and prevented mTECs and mMCs from AGE-induced loss of miR-29b and fibrotic response in vitro. Collectively, we identify that Erbb4-IR is a Smad3-dependent lncRNA that promotes renal fibrosis in T2DN by suppressing miR-29b. Targeting Erbb4-IR may represent a novel therapy for T2DN. |
| Databáze: | OpenAIRE |
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