title: Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy.
abstract: IL-1β-secreting nucleotide-binding oligomerization domain protein 3 (NLRP3) inflammasomes play a pivotal role in triggering innate immune responses in metabolic disease. We investigated the role of soluble uric acid in NLRP3 inflammasome activation in macrophages to demonstrate the effect of systemic hyperuricemia on progressive kidney damage in type 2 diabetes. THP-1 cells, human acute monocytic leukemia cells, were cultured to obtain macrophages, and HK-2 cells, human renal proximal tubule cells, were cultured and stimulated with uric acid. In vivo, we designed four rat groups as follows: 1) Long-Evans Tokushima Otsuka (LETO); 2) Otsuka Long-Evans Tokushima Fatty (OLETF); 3) OLETF+high-fructose diet (HFD) for 16 wk; and 4) OLETF+HFD+allopurinol (10 mg/dl administered in the drinking water). Soluble uric acid stimulated NLRP3 inflammasomes to produce IL-1β in macrophages. Uric acid-induced MitoSOX mediates NLRP3 activation and IL-1β secretion. IL-1β from macrophages activates NF-κB in cocultured proximal tubular cells. In vivo, intrarenal IL-1β expression and macrophage infiltration increased in HFD-fed OLETF rats. Lowering the serum uric acid level resulted in improving the albuminuria, tubular injury, macrophage infiltration, and renal IL-1β (60% of HFD-fed OLETF) independently of glycemic control. Direct activation of proximal tubular cells by uric acid resulted in (C-X-C motif) ligand 12 and high mobility group box-1 release and accelerated macrophage recruitment and the M1 phenotype. Taken together, these data support direct roles of hyperuricemia in activating NLRP3 inflammasomes in macrophages, promoting chemokine signaling in the proximal tubule and contributing to the progression of diabetic nephropathy through cross talk between macrophages and proximal tubular cells.
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Su-Mi
authors: SM
authors: Kim
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Sang-Ho
authors: SH
authors: Lee
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Yang-Gyun
authors: YG
authors: Kim
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Se-Yun
authors: SY
authors: Kim
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Jung-Woo
authors: JW
authors: Seo
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Young-Wook
authors: YW
authors: Choi
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Dong-Jin
authors: DJ
authors: Kim
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Kyung-Hwan
authors: KH
authors: Jeong
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Tae-Won
authors: TW
authors: Lee
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and.
authors: Chun-Gyoo
authors: CG
authors: Ihm
authors: Department of Pathology, Kyung Hee University, College of Medicine, Seoul, Korea.
authors: Kyu-Yeoun
authors: KY
authors: Won
authors: Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and jymoon@khu.ac.kr.
authors: Ju-Young
authors: JY
authors: Moon
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D006074:Gout Suppressants / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034622:RNA Interference; D020334:Rats, Inbred OLETF; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014527:Uric Acid / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D006074:Gout Suppressants; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C508585:IL1B protein, human; C000594089:IL1B protein, rat; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D014527:Uric Acid
keywords: NLRP3 inflammasome; diabetic nephropathy; macrophage; uric acid