Abstract:
Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy.
摘要:
高尿酸血症是慢性肾脏病(CKD)的独立危险因素,可促进肾纤维化,但是潜在的机制仍然很大程度上未知。未解决的炎症与肾纤维化密切相关,并且是众所周知的CKD进展的重要因素。包括高尿酸血症肾病。在目前的研究中,我们阐明了Caspase-11/GasderminD(GSDMD)依赖性中性粒细胞胞外陷阱(NETs)对进展性高尿酸血症性肾病的影响.我们发现Caspase-11/GSDMD信号在高尿酸性肾病的肾脏中被明显激活。Gsdmd或Caspase-11的缺失通过减少肾脏炎症来保护高尿酸血症性肾病的进展,促炎和促纤维化因子表达,NET一代,α-平滑肌肌动蛋白表达,和纤维化。此外,造血细胞中Gsdmd或Caspase-11的特异性缺失对高尿酸性肾病的肾纤维化具有保护作用。此外,体外研究揭示了尿酸诱导Caspase-11/GSDMD依赖性NETs形成的能力,从而增强巨噬细胞中α-平滑肌肌动蛋白的产生。总之,这项研究证明了Caspase-11/GSDMD通过促进NETs形成在高尿酸血症肾病进展中的作用,这可能为治疗和逆转高尿酸性肾病的治疗方法提供新的思路。