lncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy

Abstract

The role of p53 in renal fibrosis is still controversial, and its underlying mechanisms remain not clear. Here, we showed that the pharmacological inhibition and genetic deletion of p53 in proximal tubular cells can attenuate renal dysfunction, tubular epithelial disruption, and interstitial fibrosis in db/db and STZ-induced diabetic nephrology (DN) mice. In human renal proximal tubule (human kidney 2 [HK-2]) cells, inhibition of p53 by PIF reduced the high glucose (HG)-induced extracellular matrix (ECM) accumulation and reversed the inhibitory effect of HG on mRNA expression levels of lncRNA zinc finger E-box binding homeobox1-antisense RNA 1 (ZEB1-AS1) and ZEB1. Interestingly, our results demonstrated that both lncRNA ZEB1-AS1 and ZEB1 exhibited an anti-fibrotic role, while ZEB1 is positively regulated by lncRNA ZEB1-AS1 during HG treatment. Mechanistically, lnc ZEB1-AS1 bound directly to H3K4 methyltransferase myeloid and lymphoid or mixed-lineage leukemia 1 (MLL1) and promoted H3K4me3 histone modification on ZEB1 promoter, which was reduced by HG treatment. ChIP analysis indicated the binding of p53 to the promoter region of lnc ZEB1-AS1. Furthermore, the findings were verified by the kidney biopsy samples from patients with DN. Taken all together, our results suggest that p53 may be a therapeutic target for renal fibrosis in DN.

lncRNA ZEB1-AS1 inhibits high glucose-induced EMT and fibrogenesis by regulating the miR-216a-5p/BMP7 axis in diabetic nephropathy

“…ZEB1-AS1 facilitated cell migration and metastasis via targeting heterogeneous nuclear ribonucleoprotein D0 (AUF1) to activate ZEB1 expression in bladder cancer (15). Another study hinted that ZEB1-AS1 played an anti-fibrotic role in diabetic nephropathy (16). Nevertheless, the mechanism of ZEB1-AS1 in EMT and renal fibrosis of diabetic nephropathy remains unclear.…”

LncRNA ZEB1-AS1 inhibits renal fibrosis in diabetic nephropathy by regulating the miR-217/MAFB axis

“…8,9 Recently, it was shown that p53, ZEB1-AS1 and ZEB1 signaling may be involved in renal brosis in human DN. 10 However, the role and the molecular mechanism of ZEB1-AS1 in kidney brosis of human DN are still not fully understood.…”

Long noncoding RNAs in renal diseases

“…Feng et al reported that TGF-beta 1 can highly increase Erbb4-IR expression via a Smad3-dependent manner in the fibrotic kidney of mouse, suggesting that Erbb4-IR is a specific therapeutic target for chronic kidney disease [68]. Wang et al reported the lncRNA ZEB1-AS1 (zinc finger E-box binding homeobox1-antisense RNA 1) exerted an anti-fibrotic role in diabetic nephropathy [69]. Xie et al reported lncRNA H19 overexpression promoted renal fibrosis [70].…”