miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-α activation

Treatment with L-mimosine, which activates hypoxia-inducible factor-alpha (HIF-alpha), attenuates renal tubulointerstitial injury and improves renal function in a rat remnant kidney model. The miR-29 family of microRNAs directly targets a large number of extracellular matrix genes and reduces renal interstitial fibrosis. We analyzed microRNA expression profiles in rat remnant kidneys with or without treatment with L-mimosine. The expression of miR-29c was downregulated in rat remnant kidneys compared with sham control and significantly restored by the L-mimosine treatment. In cultured human kidney epithelial HK2 cells, cobalt chloride activated HIF-alpha and upregulated miR-29c expression. The upregulation of miR-29c expression was significantly attenuated by knockdown of HIF-1 alpha or HIF-2 alpha. Downregulation of miR-29c was associated with significant increases in interstitial fibrosis, collagen type II alpha 1 (COL2A1) protein, and tropomyosin 1 alpha (TPM1) protein in rat remnant kidneys and in kidneys from IgA nephropathy patients. The increases in rat remnant kidneys were attenuated by the L-mimosine treatment. COL2A1 and TPM1 were confirmed to be new, direct targets of miR-29c. In conclusion, miR-29c, an antifibrotic microRNA, is upregulated by HIF-alpha activation. MiR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by activation of HIF-alpha that attenuates fibrosis.