Gut microbiota dysbiosis in hyperuricaemia promotes renal injury through the activation of NLRP3 inflammasome.

BACKGROUND: The prevalence of hyperuricaemia (HUA), a metabolic disorder characterized by elevated levels of uric acid, is on the rise and is frequently associated with renal injury. Gut microbiota and gut-derived uremic toxins are critical mediators in the gut-kidney axis that can cause damage to kidney function. Gut dysbiosis has been implicated in various kidney diseases. However, the role and underlying mechanism of the gut microbiota in HUA-induced renal injury remain unknown. RESULTS: A HUA rat model was first established by knocking out the uricase (UOX). HUA rats exhibited apparent renal dysfunction, renal tubular injury, fibrosis, NLRP3 inflammasome activation, and impaired intestinal barrier functions. Analysis of 16S rRNA sequencing and functional prediction data revealed an abnormal gut microbiota profile and activation of pathways associated with uremic toxin production. A metabolomic analysis showed evident accumulation of gut-derived uremic toxins in the kidneys of HUA rats. Furthermore, faecal microbiota transplantation (FMT) was performed to confirm the effects of HUA-induced gut dysbiosis on renal injury. Mice recolonized with HUA microbiota exhibited severe renal injury and impaired intestinal barrier functions following renal ischemia/reperfusion (I/R) surgery. Notably, in NLRP3-knockout (NLRP3-/-) I/R mice, the deleterious effects of the HUA microbiota on renal injury and the intestinal barrier were eliminated. CONCLUSION: Our results demonstrate that HUA-induced gut dysbiosis contributes to the development of renal injury, possibly by promoting the production of gut-derived uremic toxins and subsequently activating the NLRP3 inflammasome. Our data suggest a potential therapeutic strategy for the treatment of renal diseases by targeting the gut microbiota and the NLRP3 inflammasome. Video Abstract.

The mechanism of Shenbing Decoction II against IgA nephropathy renal fibrosis revealed by UPLC-MS/MS, network pharmacology and experimental verification.

Background: IgA nephropathy (IgAN) is a major and growing public health problem. Renal fibrosis plays a vital role in the progression of IgAN. This study is to investigate the mechanisms of action underlying the therapeutic effects of Shenbing Decoction II (SBDII) in IgAN renal fibrosis treatment based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), network pharmacology and experimental verification. Method: We first used UPLC-MS/MS to explore the main compounds of SBDII, and then used network pharmacology to predict the targets and key pathways of SBDII in the treatment of IgAN renal fibrosis. Next, bovine serum albumin (BSA), lipopolysaccharide (LPS), and carbon tetrachloride (CCL4) were used to induce IgAN in rats, and then biochemical indicators, renal tissue pathology, and renal fibrosis-related indicators were examined. At the same time, part of the results predicted by network pharmacology were also verified. Result: A total of 105 compounds were identified in SBDII by UPLC-MS/MS. Network pharmacology results showed that the active compounds such as acacetin, eupatilin, and galangin may mediate the therapeutic effects of SBDII in treating IgAN by targeting tumor protein p53 (TP53) and regulating phosphatidylinositol 3-kinase (PI3K)-Akt kinase (Akt) signaling pathway. Animal experiments showed that SBDII not only significantly improved renal function and fibrosis in IgAN rats, but also significantly downregulated the expressions of p53, p-PI3K and p-Akt. Conclusion: This UPLC-MS/MS, network pharmacological and experimental study highlights that the TP53 as a target, and PI3K-Akt signaling pathway are the potential mechanism by which SBDII is involved in IgAN renal fibrosis treatment. Acacetin, eupatilin, and galangin are probable active compounds in SBDII, these results might provide valuable guidance for further studies of IgAN renal fibrosis treatment.