Sibei Tao

BACKGROUND: Sepsis is defined as end-organ dysfunction resulting from the host's inflammatory response to infection. One of the most common sepsis-injured organs is the kidneys, resulting in acute kidney injury (AKI) that contributes to the high morbidity and mortality, especially patients in the intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported to protect against the rat of lipopolysaccharide (LPS)-induced acute lung injury. However, the effect of fisetin on septic AKI remains unknown. PURPOSE: The current study proposed to systematically investigate the renoprotective effects and the underlying mechanisms of fisetin in septic AKI mice. METHODS: The model of septic AKI was established on male C57BL/6 J mice by a single intraperitoneal injection of LPS (10 mg/kg). Fisetin was administrated by gavage at 100 mg/kg for 3 consecutive days before LPS injection and the mice were sacrificed at 16 h after LPS injection. The serum and kidney samples were evaluated for biochemical analysis, histopathological examinations as well as inflammation and apoptosis related gene/protein expression. RESULTS: Pretreatment with fisetin significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in LPS-treated mice. Consistently, LPS induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by fisetin. Meanwhile, LPS injection triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, fisetin inhibited renal expression of IL-6, IL-1β, TNF-α, HMGB1, iNOS and COX-2 to improve inflammatory response. Furthermore, fisetin effectively reduced the number of TUNEL positive apoptotic cells and suppressed apoptotic protein of Bcl-2, BAX and cleaved caspase-3 in the kidneys of LPS-induced septic AKI. Mechanistically, LPS stimulated the expression of TLR4 and the phosphorylation of NF-κB p65, MAPK (p38, ERK1/2 and JNK), Src and AKT in the injured kidneys, while fisetin notably suppressed the corresponding protein expression. CONCLUSION: Fisetin alleviated kidney inflammation and apoptosis to protect against LPS-induced septic AKI mice via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways.

Background Socioeconomic status (SES) has long been conjectured to be associated with the incidence and progression of chronic kidney disease (CKD), but few studies have examined this quantitatively. This meta-analysis aims to fill this gap. Methods A systematic literature review was performed using Medline and EMBASE to identify observational studies on associations between SES and incidence and progression of CKD, published between 1974 and March 2017. Individual results were meta-analysed using a random effects model, in line with Meta-analysis of Observational Studies in Epidemiology guidelines. Results In total, 43 articles met our inclusion criteria. CKD prevalence was associated with several indicators of SES, particularly lower income (OR 1.34, 95% CI (1.18 to 1.53), P<0.001; I 2 =73.0%, P=0.05); lower education (OR 1.21, 95% CI (1.11 to 1.32), P<0.001; I 2 =45.20%, P=0.034); and lower combined SES (OR 2.18, 95% CI (1.64 to 2.89), P<0.001; I 2 =0.0%, P=0.326). Lower levels of income, occupation and combined SES were also significantly associated with progression to end-stage renal disease (risk ratio (RR) 1.24, 95% CI (1.12 to 1.37), P<0.001; I 2 =66.6%, P=0.006; RR 1.05, 95% CI (1.01 to 1.09), P=0.012; I 2 =0.0%, P=0.796; and RR 1.39, 95% CI (1.09 to 1.79), P=0.009; I 2 =74.2%, P=0.009). Subgroup analyses generally confirmed these results, except in a few cases, such as an inverse association related to particular socioeconomic backgrounds and where results were adjusted by more disease-related risk factors. Conclusion Lower income was most closely associated with prevalence and progression of CKD, and lower education was significantly associated with its prevalence. Evidence for other indicators was inconclusive.

Acute kidney injury (AKI) is a serious clinical complication with high morbidity and mortality rates. Despite substantial progress in understanding the mechanism of AKI, no effective therapy is available for treatment or prevention. We previously found that G protein-coupled receptor (GPCR) family member free fatty acid receptor 4 (FFAR4) agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice. However, the versatile role of FFAR4 in kidney has not been well characterized. In the study, the expression of FFAR4 was abnormally decreased in tubular epithelial cells (TECs) of cisplatin, cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice. Notably, FFAR4, as a key determinant, was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, marker protein p53, p21, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs. These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.