Abstract
Podocyte injury critically contributes to the pathogenesis of obesity-related glomerulopathy (ORG). Recently, lipid accumulation and inflammatory responses have been found to be involved in podocyte injury. This study is to explore their role and relationship in podocyte injury of ORG. In animal experiments, the ORG mice developed proteinuria, podocyte injury, and hypertriglyceridemia, accompanied with deregulated lipid metabolism, renal ectopic lipid deposition, activation of NOD-like receptor protein 3 (NLRP3) inflammasome, and secretion of IL-1β of the kidney. The expression of adipose differentiation-related protein (ADRP), CD36, sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor α (PPARα) in renal tissue were increased. In in vitro cell experiments, after cultured podocytes were stimulated with leptin, similar to ORG mice, we found aggravated podocyte injury, formatted lipid droplet, increased expression of ADRP and CD36, activated NLRP3 inflammasome, and released IL-1β. In addition, after blocking CD36 with inhibitor sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA, activation of NLRP3 inflammasome and release of IL-1β are downregulated, and podocyte injury was alleviated. However, after blocking NLRP3 with MCC950, although podocyte injury was alleviated and release of IL-1β was decreased, there was no change in the expression of CD36, ADRP, and intracellular lipid droplets. Taken together, our study suggests that CD36-mediated lipid accumulation and activation of NLRP3 inflammasome may be one of the potential pathogeneses of ORG podocyte injury.
Highlights
Obesity is one of the major public health concerns with prevalence rates rapidly rising worldwide
Glomerular hypertrophy accompanied with podocyte hypertrophy and podocyte process fusion are the main pathological features of obesity-related glomerulopathy (ORG), secondary focal segmental glomerulosclerosis may have occurred on this pathological basis, and clinical manifestations are proteinuria and progressive renal dysfunction; some patients may eventually develop end-stage renal disease (ESRD) [2, 3]
Is CD36-mediated lipid accumulation involved in podocyte injury of ORG? Is it associated with NOD-like receptor protein 3 (NLRP3) inflammasome activation? Our study showed that both in ORG mouse models and in leptin-stimulated cultured podocytes, formatted lipid droplets, increased expression of adipose differentiationrelated protein (ADRP) and CD36, activated NLRP3 inflammasome, and released IL-1β were found
Summary
Obesity is one of the major public health concerns with prevalence rates rapidly rising worldwide. In China, according to the 2010 China chronic disease monitoring program, the prevalence of obesity and central obesity of Chinese adults is 12.0% and 40.7%, respectively [1]. Obesity may directly lead to kidney injury, known as obesity-related glomerulopathy (ORG), and the incidence of ORG has increased concurrently with obesity [2, 3]. A retrospective study by D’Agati et al showed that among cases that underwent renal biopsy, the percentage of ORG increased 13.5 times from 1986 to 2015 [3]. We analyzed the cases that underwent renal biopsy in our hospital from 2010 to 2015 and calculated that the incidence of ORG with or without other kidney diseases accounted for 9.85% [4]. Podocyte injury critically contributes to the pathogenesis of ORG. Glomerular hypertrophy accompanied with podocyte hypertrophy and podocyte process fusion are the main pathological features of ORG, secondary focal segmental glomerulosclerosis may have occurred on this pathological basis, and clinical manifestations are proteinuria and progressive renal dysfunction; some patients may eventually develop end-stage renal disease (ESRD) [2, 3]
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