Nlrp3 is a key modulator of diet-induced nephropathy and renal cholesterol accumulation

Abstract

Metabolic syndrome (MetSyn) is a major health concern and associates with the development of kidney disease. The mechanisms linking MetSyn to renal disease have not been fully elucidated but are known to involve hyperuricemia, inflammation, and fibrosis. Since the innate immune receptor Nlrp3 is an important mediator of obesity and inflammation, we sought to determine whether Nlrp3 is involved in the development of MetSyn-associated nephropathy by giving wild-type or Nlrp3-knockout mice a Western-style compared to a normal diet or water without or with fructose. A plausible driver of pathology, the Nlrp3-dependent cytokine IL-1β was not increased in the kidney. Interestingly, Nlrp3-dependent renal cholesterol accumulation, another well-known driver of renal pathology, was enhanced during MetSyn. We also determined the role of Nlrp3 and fructose-fortified water on the development of MetSyn and kidney function since fructose is an important driver of obesity and kidney disease. Surprisingly, fructose did not induce MetSyn but, irrespective of this, did induce Nlrp3-dependent renal inflammation. The presence of Nlrp3 was crucial for the development of Western-style diet-induced renal pathology as reflected by the prevention of renal inflammation, fibrosis, steatosis, microalbuminuria, and hyperuricemia in the Nlrp3-knockout mice. Thus, Nlrp3 may mediate renal pathology in the context of diet-induced MetSyn.

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

“…SREBP1 hyperactivity and NLPR3 inflammasome activation in lesions are detected in atherosclerotic pig aortas with vascular inflammation (23). Studies by us and others showed that fructose induced NLRP3-dependent renal inflammation and steatosisassociated metabolic syndrome (1,14). In this study, inhibition of NLRP3 expression and caspase-1 activity reverted fructose-induced transcriptomic dysregulation of PPAR-a, SREBP1, and SCD1 in hepatocytes, suggesting that NLRP3 inflammasome activation plays a role in fructose-induced aberrations in hepatocellular lipid metabolism.…”

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

“…These results are consistent with other reports showing noncanonical effects of Nlrp3 in the kidney. 15,16,27,29 Next to cytokines, renal function is influenced by tubular damage and repair. Interestingly, we observed that renal apoptosis was reduced in mice lacking Nlrp3 expression in leukocytes, suggesting that leukocyte-associated Nlrp3 influences tubular epithelial apoptosis and, thereby, renal dysfunction.…”

NLRP3 Inflammasome Mediates Albumin-induced Renal Tubular Injury through Impaired Mitochondrial Function

“…The activation of NLRP3 inflammasome finally triggers the maturation of IL-1␤ and IL-18 via activated caspase-1. Growing evidence indicates that the NLRP3 inflammasome is associated with the progression of kidney diseases (12)(13)(14). Recently, several reports have further demonstrated that activation of inflammasome can be regulated by a mitochondrial mechanism (8,15,16).…”