Abstract
Background Renal interstitial fibrosis is a pathological manifestation of progression of chronic kidney disease induced by various factors. Shen Shuai II Recipe (SSR) has been used in clinical practice for more than 20 years, and clinical studies have confirmed that SSR significantly improves the renal function of patients with chronic kidney disease. However, the specific mechanisms underlying its efficacy require further research. This study aims to explore the influencing factors of renal interstitial fibrosis in the context of hypoxia via the IL-1β/c-Myc pathway and the potential molecular mechanisms of SSR intervention in vivo and in vitro. Methods A rat model of chronic renal failure was developed by performing 5/6 (ablation/infarction, A/I) surgery on randomly selected, male Sprague Dawley rats. Thirty-six successfully modeled rats were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + SSR, and 5/6 (A/I) + losartan. Another 12 rats were used as the sham group. After 8 weeks of the corresponding intervention, renal function, liver function, and protein expression of renal-fibrosis-related factors, HIF-1α, IL-1β, and c-Myc, were detected. In vitro analysis was performed using hypoxia-induced rat renal tubular epithelial cells (NRK-52E) and IL-1β-stimulated rat renal interstitial fibroblasts (NRK-49F). IL-1β concentration in the culture medium and IL-1β protein expression in hypoxic NRK-52E treated with different concentrations of SSR were investigated. Furthermore, we also studied the changes in protein expression of c-Myc and fibrosis-related factors after c-Myc gene silencing in IL-1β-stimulated NRK-49F treated with SSR. Results Shen Shuai II Recipe significantly reduced RIF and downregulated the expression of HIF-1α, c-Myc, and IL-1β proteins in 5/6 (A/I) rats with chronic renal failure. It also inhibited IL-1β secretion from NRK-52E induced by hypoxia, which in turn inhibited fibroblast activation mediated by the IL-1β/c-Myc pathway, and finally reduced the overproduction of the extracellular matrix. Conclusion The renoprotective effects of SSR in rats with chronic renal failure may be related to its inhibition of hypoxia via the IL-1β/c-Myc pathway. Thus, SSR is a potentially effective drug for delaying the progression of renal interstitial fibrosis.
Highlights
Chronic kidney disease (CKD), a major global health problem with high morbidity and mortality, places a huge economic burden on families and society [1, 2]
Drugs. e composition of Shen Shuai II Recipe (SSR) is shown in Table 1. e raw herbs were purchased from Shanghai Kangqiao Chinese Medicine Tablet Co., Ltd. and identified by Dr Guanglin Xu from the Department of Pharmacy, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine (SHUTCM). e SSR was prepared as previously described [19], and the final concentration of the original drug was 4 g/mL. e positive control group losartan
Four weeks after the establishment of the rat model, serum creatinine (Scr) and UREA of the operated rats significantly increased (Figure 2(a)), indicating that the model was successful. e blood biochemical detection results after treatment suggested that renal indexes such as Scr and UREA were significantly higher in the model group than in the other groups. ere was no significant difference in the levels of ALT and aspartate transaminase (AST) among different groups (Figure 2(b))
Summary
Chronic kidney disease (CKD), a major global health problem with high morbidity and mortality, places a huge economic burden on families and society [1, 2]. Renal interstitial fibrosis is a pathological manifestation of progression of chronic kidney disease induced by various factors. Is study aims to explore the influencing factors of renal interstitial fibrosis in the context of hypoxia via the IL-1β/c-Myc pathway and the potential molecular mechanisms of SSR intervention in vivo and in vitro. Shen Shuai II Recipe significantly reduced RIF and downregulated the expression of HIF-1α, c-Myc, and IL-1β proteins in 5/6 (A/ I) rats with chronic renal failure. It inhibited IL-1β secretion from NRK-52E induced by hypoxia, which in turn inhibited fibroblast activation mediated by the IL-1β/c-Myc pathway, and reduced the overproduction of the extracellular matrix. Conclusion. e renoprotective effects of SSR in rats with chronic renal failure may be related to its inhibition of hypoxia via the IL-1β/c-Myc pathway. us, SSR is a potentially effective drug for delaying the progression of renal interstitial fibrosis
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