Astragaloside IV/lncRNA-TUG1/TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats

Abstract

ObjectiveThis study aims to figure out the mechanism of astragaloside IV (AS-IV) in the protection of podocyte apoptosis in diabetic nephropathy (DN) rats.Materials and methodsStreptozotocin (STZ) was used to induce diabetes in rats, and the diabetic rats were treated with 5 mg/kg/d of AS-IV for 12 weeks. Albuminuria level, relative TUG1 and TRAF5 levels, and TRAF5 and cleaved-caspase-3 protein levels were examined by ELISA, quantitative reverse transcription (qRT)-PCR, and Western blot analyses, respectively. The interaction between TUG1 and TRAF5 was confirmed by RNA pull-down and RNA precipitation. TUNEL assay was used to detect podocyte apoptosis.ResultsCompared with control rats, DN rats had higher albuminuria and TRAF5 levels and lower TUG1 level. AS-IV treatment attenuated albuminuria and TRAF5 levels and improved TUG1 level in DN rats. TUG1 was downregulated and TRAF5 was upregulated in high-glucose-treated MPC5 cells, and AS-IV ameliorated the TUG1 level. In addition, TUG1 interacted with TRAF5, and TUG1 overexpression promoted degradation of TRAF5 protein. Besides, AS-IV modulated TRAF5 expression through regulating TUG1. AS-IV decreased podocyte apoptosis via the TUG1/TRAF5 pathway. Finally, in vivo experiment proved that si-TUG1 abrogated the protective effect of AS-IV on DN.ConclusionAS-IV attenuated podocyte apoptosis and protected diabetic rats from DN via the lncRNA-TUG1/TRAF5 pathway.

Interactions Among Non-Coding RNAs in Diabetic Nephropathy

“…LncRNA GAS5 is also a proapoptotic lncRNA, in which GAS5 promoted the human renal tubular epithelial cells apoptosis under high glucose environment (Lv et al, 2019) In contrast to that, lncRNA GM15645 expression was low in DN mice and podocyte cells upon stimulation of high glucose, and this lncRNA acts opposite to lncRNA GM5524 in the regulation of podocyte cells apoptosis and autophagy (Feng et al, 2018). Similar to the anti-apoptotic effects of GM15645, lncRNA Taurine upregulated-1 (TUG-1), was downregulated in the DN and hyperglycemic condition, with evidence of renal damage and loss of podocyte cells in DN patients and animal model (Lei et al, 2018;Shen et al, 2019). Loss of TUG-1 expression reduces peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) expression, as TUG-1 binds to the promoter region of the Ppargc1a gene to increase its expression (Long et al, 2016).…”

“…Loss of TUG-1 expression reduces peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) expression, as TUG-1 binds to the promoter region of the Ppargc1a gene to increase its expression (Long et al, 2016). Consequently, loss of TUG-1 expression increases the tumor necrosis factor receptorassociated factor 5 (Traf5) expression and stimulates the podocyte cell death (Lei et al, 2018). Restoration of TUG-1 expression inhibits Traf5 protein production, not its mRNAs expression, and ameliorates podocyte cell survival (Lei et al, 2018).…”

“…Consequently, loss of TUG-1 expression increases the tumor necrosis factor receptorassociated factor 5 (Traf5) expression and stimulates the podocyte cell death (Lei et al, 2018). Restoration of TUG-1 expression inhibits Traf5 protein production, not its mRNAs expression, and ameliorates podocyte cell survival (Lei et al, 2018). Another anti-apoptotic lncRNA is lncRNA NR_033515, in which its circulating expression was higher in DN patients, and this NR_033515 lncRNA can inhibit apoptosis by increasing the expression of proliferation genes (PCNA and CCND1) and fibrotic genes (P38, ASK1, FN, and a-SMA) (Gao et al, 2018).…”

Mechanism of NHX1 Inhibiting TRPV5-Mediated Podocyte Injury in Diabetic Nephropathy

“…Previous studies have shown that [8], NHX1 can convert the phosphate group into GTP in GDP, which activates Ras. NHX1 protein is expressed in the glomeruli and renal tubules of human kidneys [9]. In 2016, a large-scale exome analysis showed that NHX1 regulates kidney development and function [10].…”

Long noncoding RNAs in renal diseases

“…Reducing MALAT1 levels can improve renal functions after duodenal-jejunal bypass in diabetic rats [79]. Increasing expression of lncRNA TUG1 (taurine upregulated gene 1) can attenuate podocyte apoptosis, alleviate extracellular matrix accumulation and protect diabetic rats from DN [80,81]. Besides, TUG1 was also reported to regulate mitochondrial bioenergetics in DN [82].…”