Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China.
Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215000, China.
Dis Model Mech. 2021 Mar 24;14(3):dmm048041. doi: 10.1242/dmm.048041.
Epidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease; however, the mechanisms underlying this process have not yet been elucidated. To examine the role of urate in the kidney, we used Wistar rats to functionally disrupt expression of urate oxidase (UOX) by using the CRISPR/Cas9 system. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in -KO rats, without showing a significant decrease in survival rate. Architecture and function of the kidneys in -KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, increased expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, such as AMPK, p38 MAPK, ERK and JNK pathways. Inhibition of autophagy with the PI3K inhibitor 3-MA abrogated the development of kidney damage and attenuated renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys. In conclusion, the -KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3-dependent inflammation are critically involved in the development of renal damage and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy.
流行病学研究表明，血清尿酸浓度升高是肾脏疾病发展的一个危险因素；然而，这一过程的机制尚未阐明。为了研究尿酸在肾脏中的作用，我们使用 CRISPR/Cas9 系统使 Wistar 大鼠尿酸氧化酶（UOX）的表达功能性缺失。与野生型（WT）大鼠相比，-KO 大鼠的血清尿酸水平自发且持续升高，而存活率没有明显下降。-KO 大鼠的肾脏结构和功能受损。肾脏损伤导致间质纤维化、巨噬细胞浸润增加，NLRP3 和 IL-1β 的表达增加，以及与自噬相关的多个细胞信号通路的激活，如 AMPK、p38 MAPK、ERK 和 JNK 通路。用 PI3K 抑制剂 3-MA 抑制自噬可阻断肾脏损伤的发展，并减轻肾脏纤维化、巨噬细胞浸润以及损伤肾脏中 NLRP3 和 IL-1β 的表达。总之，-KO 大鼠是研究高尿酸血症相关疾病的理想模型。高尿酸血症诱导的自噬和 NLRP3 依赖性炎症在肾脏损伤的发展中起着至关重要的作用，因此，强调抑制自噬和炎症，以寻找治疗尿酸肾病的治疗策略。
