Ginsenoside Rg1 Protects Chronic Cyclosporin A Nephropathy From Tubular Cell Apoptosis by Inhibiting Endoplasmic Reticulum Stress in Rats

• Consistent with the previous reports, our investigations successfully reported the close link between apoptosis and interstitial fibrosis in a rat model of chronic cyclosporin A (CsA) nephropathy. We observed that CsA treatment caused striped fibrosis in interstitium as detected by Masson's trichrome staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling–positive numbers were substantially increased and the expression of caspase-3 protein was markedly up-regulated after chronic CsA treatment.
• We assessed the expression of the endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) in rat kidneys after CsA treatment. We found that GRP78 and CHOP protein were increased in the kidneys of rats with CsA treatment for 28 days. These findings show that chronic CsA therapy accelerates renal fibrosis development associated with CHOP-mediated tubular cell apoptosis, indicating that ER stress may be significantly involved in the pathophysiology of tubulointerstitial damage in chronic CsA nephropathy.
• Using a rat model of chronic CsA nephrotoxicity, we observed that ginsenoside Rg1 (G-Rg1) administration decreased GRP78 and CHOP expression in protein levels; meanwhile, it increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling–positive tubular cells and the level of caspase-3. These findings indicate that the therapeutic effects of G-Rg1 on CsA nephrotoxicity are probably due to inverting the relation of ER stress–triggered apoptosis into an antiapoptotic pathway.

IntroductionThis study tested the effect of ginsenoside Rg1 (G-Rg1) in cyclosporin A (CsA)-induced endoplasmic reticulum (ER) stress on renal tubular cell apoptosis in a rat model of chronic CsA nephropathy.Materials and MethodsTwenty-two Sprague-Dawley rats were randomized into 3 groups: a control group, a model group (CsA 25 mg/kg per day), and a G-Rg1 treatment group (CsA 25 mg/kg per day and G-Rg1 20 mg/kg per day). We examined the effects of G-Rg1 on histopathology, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, and expression of glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, and caspase-3 by using Western blot analysis.ResultsG-Rg1 attenuated CsA-induced tubulointerstitial fibrosis and reduced tubular epithelial cell apoptosis as assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and caspase-3 expression. Compared with the model group, it reduced the expression of glucose-regulated protein 78 and CCAAT/enhancer-binding protein homologous protein (0.12 ± 0.03 vs 0.48 ± 0.05 [P < .01]; 0.55 ± 0.11 vs 1.08 ± 0.07 [P < .05]), respectively.ConclusionsG-Rg1 mitigates the progression of chronic CsA nephropathy, at least in part, through inhibition of ER stress–triggered tubular cell apoptosis.