Shen Shuai II Recipe Attenuates Renal Interstitial Fibrosis by Improving Hypoxia via the IL-1β/c-Myc Pathway

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.

Shen Shuai II recipe improves renal hypoxia to attenuate renal injury in 5/6 renal ablation/infarction rats and effect evaluation using blood oxygenation level-dependent functional magnetic resonance imaging

“…The major chemical components of SSR, identified by Ultra-High Performance Liquid Chromatography-High Resolution Mass Spectrometry, was reported in our previous study [ 7 ], including rosmarinic acid (21.280 mg/each gram of SSR), amygdalin (6.588 mg/g), salvianolic acid B (1.852 mg/g), caffeic acid (1.390 mg/g), icariin (1.055 mg/g), berberine hydrochloride (0.503 mg/g), codonopsis lactone (0.130 mg/g), ferulic acid (0.127 mg/g), emodin (0.111 mg/g), and tanshinone IIA (0.005 mg/g).…”

“…The properties of SSR are including tonifying the spleen and kidney, clearing heat and dampness, and activating blood circulation to resolve stasis. Our previous experimental studies have demonstrated that SSR has potential anti-inflammatory and antifibrotic effects under renal hypoxia condition [ 7–8 ]. Additionally, we found that SSR could improve renal perfusion and reduce renal oxygen consumption in 5/6 renal ablation/infarction (A/I) rats [ 9 ].…”