Protective mechanism of traditional Chinese medicine guizhi fuling pills against carbon tetrachloride-induced kidney damage is through inhibiting oxidative stress, inflammation and regulating the intestinal flora

Chemical or drug-induced kidney damage has been recognized as a critical cause of kidney failure. The oxidative stress, inflammation, and imbalance of intestinal flora caused by carbon tetrachloride (CCl4) play a fundamental role in chronic kidney damage. Guizhi Fuling pills (GZFL) is a traditional formula consisting of five traditional Chinese medicinal herbs, which can promote blood circulation and improve kidney function. The underlying mechanisms of GZFL improving kidney damage are not fully understood yet.The current study aimed to explore the effects of GZFL on CCl4-induced kidney damage and intestinal microbiota in mice.Male ICR mice were intraperitoneally administered with 20% CCl4 (mixed in a ratio of 1:4 in soybean oil) twice a week, for 4 weeks to induce kidney damage. Creatinine (CRE), urea nitrogen, antioxidant enzymes, and inflammatory cytokines were measured and the histology of the kidney, jejunum, and colon examination to assess kidney and intestinal damage. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) family members, nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in kidney tissues, and the tight junction proteins in colonic tissues were detected by Western blot. The gut microbiota was analyzed through 16S rRNA gene sequencing.GZFL treatment decreased the serum CRE and urea nitrogen levels. Moreover, GZFL reduced the levels of pro-inflammatory cytokines and increased antioxidant enzyme activities in kidney and colonic tissues. GZFL improved the kidney, jejunum, and colon histology. Furthermore, GZFL inhibited the expressions of NLRP3, ASC, and cleaved-Caspase-1, while Nrf2, HO-1, NQO1, GCLM, and tight junction proteins were increased. The dysbiosis of intestinal microbiota improved after GZFL treatment.This study showed that GZFL could improve kidney damage, which might be mainly via the integrated regulations of the Nrf2 pathway, NLRP3 inflammasome, and composition of intestinal microbiota.