The HIF-1α/miR-145b/Angpt2 axis attenuates renal fibrosis induced by unilateral renal ischemia–reperfusion

Abstract

Abstract Background Renal fibrosis is a major pathological feature in chronic kidney disease, and is considered the final common pathway for virtually all progressive kidney diseases. Although a large amount of progress has been made in understanding renal fibrosis, the pathogenesis is very complex and still incompletely understood. Methods Renal fibrosis was induced by unilateral renal ischemia–reperfusion (uIR) operation. In some experiments, microRNA-145b (miR-145b) mimic or locked nucleic-acid-modified (LNA-modified) anti-miR-145b was delivered to mice through tail vein injection every 2 days, for a total of seven injections following uIR operation. In some experiments, YC-1 (a selective HIF-1α inhibitor) was given intraperitoneally on the day of uIR operation and continued until the mice were euthanized. The mice were euthanized 2 weeks after uIR operation for further analysis. Results We demonstrated a significant increase of microRNA-145b (miR-145b) in renal tubular cells in mice following a uIR operation. The uIR operation led to the activation of HIF-1α in renal tubular cells, and inhibition of HIF-1α prevented the increase of miR-145b. Chromatin immunoprecipitation (ChIP) assays further verified HIF-1α directly binding to the miR-145b gene promoter upon uIR operation. Functionally, inhibiting miR-145b using locked nucleic-acid-modified (LNA-modified) anti-miR-145b could aggravate renal tubular injury and promote the progression of renal fibrosis following uIR operation, indicating that miR-145b serves as an anti-fibrotic factor. Further, our study also found miR-145b in vivo transfection suppressed the expression of angiopoietin-2 (Angpt2) in mice after uIR operation. Luciferase microRNA target reporter assays further verified Angpt2 as a direct target of miR-145b. Conclusions This study unveiled a HIF-1α/microRNA-145b/Angpt2 axis that could ameliorate tubular injury and delay the development and progression of renal fibrosis.

Keywords

• Renal fibrosis
• miR-145b
• HIF-1α
• Angpt2
• Unilateral renal ischemia–reperfusion