Abstract
Hyperuricemia has become a common metabolic disease, and is a risk factor for multiple diseases, including chronic kidney disease. Our recent study indicated that following persistent uric acid stimulation, autophagy was activated in rats of hyperuricemic nephropathy (HN) and facilitated the development of renal fibrosis. Nevertheless, the potential mechanism by which autophagy promoted the progression of HN is still not fully elucidated. Thus, in the current study, we investigated the mechanisms of autophagy inhibition on the development of HN. Our data showed that autophagy was activated in human renal tubular cell lines (HK-2) exposure to uric acid. Inhibition of autophagy with 3-methyladenine (3-MA) and transfected with Beclin-1 siRNA prevented uric acid-induced upregulation of α-SMA, Collagen I and Collagen III in HK-2 cells. Moreover, uric acid upregulated autophagy via promoting the p53 pathway. In vivo, we showed that hyperuricemic injury induced the activation of NLRP3 inflammasome and pyroptosis, as evidenced by cleavage of caspase-1 and caspase-11, activation of gasdermin D (GSDMD) and the release of IL-1β and IL-18. Treatment with autophagy inhibitor 3-MA alleviated aforementioned phenomenon. Stimulation with uric acid in HK-2 cells also resulted in NLRP3 inflammasome activation and pyroptotic cell death, however treatment with 3-MA prevented all these responses. Mechanistically, we showed that the elevation of autophagy and degradation of autophagolysosomes resulted in the release of cathepsin B (CTSB), which is related to the activation of NLRP3 inflammasome. CTSB siRNA can inhibit the activation of NLRP3 inflammasome and pyroptosis. Collectively, our results indicate that autophagy inhibition protects against HN through inhibiting NLRP3 inflammasome-mediated pyroptosis. What’s more, blockade the release of CTSB plays a crucial role in this process. Thus, inhibition of autophagy may be a promising therapeutic strategy for hyperuricemic nephropathy.
Highlights
With the rapid development of the world economic and the improvement of lifestyle, the prevalence of hyperuricemia is remarkably increasing all over the world [1, 2]
Since epithelialto-mesenchymal transition (EMT) is involved in the progression of renal fibrosis [24], we found that compared with serumstarved HK-2 cells, uric acid-exposed HK-2 cells expressed higher protein levels of a-SMA, Collagen I, and Collagen III, three mesenchymal markers
Inhibition of autophagy with 3-MA significantly reduced the expression of a-SMA, Collagen I, and Collagen III (Figures 1F–I). Consistent with this result, knocking down of Beclin-1 blocked the expression of a-SMA and Collagen I (Figures 1M–O). These results indicated that autophagy was activated in the uric acidstimulated HK-2 cells, which is essential for the occurred of EMT in tubular epithelial cells
Summary
With the rapid development of the world economic and the improvement of lifestyle, the prevalence of hyperuricemia is remarkably increasing all over the world [1, 2]. About 75% of uric acid is excreted by the kidneys, and chronic uric acid stimulation to the kidney results in renal tubule-interstitial fibrosis, eventually causes hyperuricemic nephropathy (HN) [3]. The treatment of HN mainly focuses on the drugs that suppress the production of uric acid and promote the excretion of uric acid, such as the first-line drugs allopurinol and benzbromarone respectively. Their clinical applications are limited by the severe side effects, such as hepatotoxicity, nephrotoxicity, and Stevens-Jonson syndrome [6], using uric acid-lowering agents in HN is still controversial [7]. It is imperative to search appropriate therapeutic strategy for HN
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