Hyperuricemia causes kidney damage by promoting autophagy and NLRP3-mediated inflammation in rats with urate oxidase deficiency
Epidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease, but the mechanisms underlying this process have not been elucidated. To examine the role of urate in the kidney, we performed functional disruption of urate oxidase (UOX) using the CRISPR/Cas9 system in Wistar rats. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in UOX-KO rats without a significant decrease in survival rate. The architecture and function of the kidneys in UOX-KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, including the AMPK, p38 MAPK, ERK, and JNK pathways. Inhibition of autophagy with 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 UOX-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. The inhibition of autophagy and inflammation are potential therapeutic strategies for uric acid nephropathy.