Novel lncRNA Erbb4-IR Promotes Diabetic Kidney Injury in db/db Mice by Targeting miR-29b
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AbstractTransforming growth factor-beta/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 39 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.
Acceptance Date30/11/2017
All Author(s) ListSi F. Sun, Patrick M.K. Tang, Min Feng, Jun Xiao, Xiao R. Huang, Ping Li, Ronald C.W. Ma, Hui Y. Lan
Journal nameDiabetes
Volume Number67
Issue Number4
PublisherAmerican Diabetes Association
Pages731 - 744
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesEndocrinology & Metabolism;Endocrinology & Metabolism

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