poricoic-acid-a and Renal-Insufficiency--Chronic

Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.

Topics: Acute Kidney Injury; Animals; Antioxidants; Biomarkers; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Kidney; Male; Melatonin; NF-E2-Related Factor 2; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases; Renal Insufficiency, Chronic; Reperfusion Injury; Triterpenes

Dysbiosis of the gut microbiome and related metabolites in chronic kidney disease (CKD) have been intimately associated with the prevalence of cardiovascular diseases. Unfortunately, thus far, there is a paucity of sufficient knowledge of gut microbiome and related metabolites on CKD progression partly due to the severely limited investigations. Using a 5/6 nephrectomized (NX) rat model, we carried out 16S rRNA sequence and untargeted metabolomic analyses to explore the relationship between colon's microbiota and serum metabolites. Marked decline in microbial diversity and richness was accompanied by significant changes in 291 serum metabolites, which were mediated by altered enzymatic activities and dysregulations of lipids, amino acids, bile acids and polyamines metabolisms. Interestingly, CCr was directly associated with some microbial genera and polyamine metabolism. However, SBP was directly related to certain microbial genera and glycine-conjugated metabolites in CKD rats. Administration of poricoic acid A (PAA) and Poria cocos (PC) ameliorated microbial dysbiosis as well as attenuated hypertension and renal fibrosis. In addition, treatments with PAA and PC lowered serum levels of microbial-derived products including glycine-conjugated compounds and polyamine metabolites. Collectively, the present study confirmed the CKD-associated gut microbial dysbiosis and identified a novel dietary and therapeutic strategy to improve the gut microbial dysbiosis and the associated metabolomic disorders and retarded the progression of kidney disease in the rat model of CKD.

Topics: Animals; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Glycine; Humans; Hypertension; Male; Metabolome; Metabolomics; Polyamines; Rats; Renal Insufficiency, Chronic; Triterpenes; Wolfiporia