Hyperuricemia causes kidney damage by promoting autophagy and NLRP3-mediated inflammation in rats with urate oxidase deficiency
Open Access
- 1 March 2021
- journal article
- research article
- Published by The Company of Biologists in Disease Models & Mechanisms
- Vol. 14 (3)
- https://doi.org/10.1242/dmm.048041
Abstract
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 UOX-KO rats, without showing a significant decrease in survival rate. Architecture and function of the kidneys in UOX-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 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 and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy.Keywords
Funding Information
- Key Technologies Research and Development Program (2019YFA0904500)
- National Natural Science Foundation of China (81670737, 81870616)
This publication has 33 references indexed in Scilit:
- Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathyAmerican Journal of Physiology-Renal Physiology, 2015
- Genome modification by CRISPR/Cas9The FEBS Journal, 2014
- Enhanced p62 expression through impaired proteasomal degradation is involved in caspase-1 activation in monosodium urate crystal-induced interleukin-1 expressionRheumatology, 2014
- Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injuryThe EMBO Journal, 2013
- Monosodium Urate Activates Src/Pyk2/PI3 Kinase and Cathepsin Dependent Unconventional Protein Secretion From Human Primary MacrophagesMolecular & Cellular Proteomics, 2013
- Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling PathwayPLOS ONE, 2012
- Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destructionNature Immunology, 2012
- Elevated Uric Acid Increases the Risk for Kidney DiseaseJournal of the American Society of Nephrology, 2008
- Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β productionNature, 2008
- Gout-associated uric acid crystals activate the NALP3 inflammasomeNature, 2006