Yiqi Huoxue Tongluo recipe regulates NR4A1 to improve renal mitochondrial function in unilateral ureteral obstruction (UUO) rats

Abstract

Context Yiqi Huoxue Tongluo recipe (YHTR) is a traditional Chinese medicine for the treatment of chronic kidney disease, but its exact mechanism is not clear. Objectives To monitor the potential improvement of renal mitochondrial function in unilateral ureteral obstruction (UUO) rats by regulating NR4A1 using the YHTR. Materials and methods Wistar rats were randomly divided into four groups: sham, UUO (left ureteral ligation for 14 days), eplerenone (EPL) (UUO + EPL), and YHTR (UUO + YHTR). UUO rats were established and intragastrically administered EPL (100 mg/day/kg) or YHTR (11.7 g/day/kg) for 14 days. The expression of related proteins in kidneys was detected by immunohistochemistry, western blot, RT-PCR, and chemical colorimetric assay, respectively. Results In vivo , YHTR treatment reduced the levels of BUN and Scr (by 17.9% and 23.5%) in UUO rats. Moreover, YHTR improved the renal mitochondrial function via increasing key enzymes of the tricarboxylic acid (TCA) cycle ( p < 0.05) and activity of the mitochondrial complex (I–V) (by 30.8%, 29.1%, 19.7%, 35.9%, and 22.4%) in UUO rats. Compared with the UUO group, the expression of NR4A1 and Bcl-2 were significantly increased ( p < 0.05), the expression of caspase-3 and caspase-9 were significantly decreased ( p < 0.05) in the YHTR group. YHTR could upregulate key enzymes of the TCA cycle via promoting NR4A1 expression in HK2 cells, leading to inhibition of TGF-β1 induced cell apoptosis. Conclusions YHTR significantly improved the development of CKD; this study may provide new ideas for the pathogenesis of CKD and new strategies for the development of new drugs against CKD.

Single cell multi-omics of fibrotic kidney reveal epigenetic regulation of antioxidation and apoptosis within proximal tubule

“…Our research also found high NR4A1 activities in the con kidney compared with uuo kidney in the snATAC-seq data. As we know, the nuclear receptor NR4A1, as an endogenous inhibitor of TGF-β signaling, can improve kidney fibrosis in mice [43], meanwhile, NR4A1 can upregulate the key enzymes of the TCA cycle which was found to be downregulated in uuo sample of this analysis [44].…”