Obesity has been reported to be associated with glomerular injury and ultimate end-stage renal disease (ESRD). Although hypertension or diabetes mellitus in obesity may contribute to the development of ESRD, the molecular mechanisms of obesity-induced renal injury, in particular, the early mechanisms mediating glomerular injury that occur prior to hypertension and diabetes are still poorly understood. In thi grant proposal, we attempt to elucidate an early intracellular molecular mechanism, namely, the Nalp3 inflammasome activation, which may switch on glomerular injury through its inflammatory or non-inflammatory pathway leading to glomerular dysfunction and ultimately sclerosis during obesity. Interestingly, our preliminary studies demonstrated that obesity-induces the Nalp3 inflammasome activation and contributes to the glomerular injury independent of elevated arterial blood pressure and have also shown that beyond inflammation, the activated inflammasomes have direct actions on the podocytes. This may represent a novel pathogenic mechanism of inflammasome activation beyond inflammation. Based on these observations, we hypothesize that obesity increases visfatin production and thereby activates Nalp3 inflammasomes in podocytes to produce IL-1 stimulating inflammatory response in glomeruli and initiating direct podocyte damage, ultimately resulting in glomerular injury and sclerosis. To test this hypothesis, we will first determine whether obesity-induced Nalp3 inflammasome formation and activation contribute to glomerular injury in vivo prior to hypertension in experimental high fat diet (HFD)-induced obesity using Asc-/- mice with or without rescuing Asc gene and wild type mice with and without locally silencing Asc gene. We will then examine how Nalp3 inflammasomes are activated in podocytes with a focus on the role of adipokine visfatin in cultured podocytes and in vivo in mice and to elucidate its functional significance in inflammasome activation. Finally, we will explore the mechanisms by which activated Nalp3 inflammasomes lead to podocyte injury and glomerular dysfunction or sclerosis by studying the actions of inflammasome products such as IL-1, IL-18, pyroptosis and DAMPs in cultured podocytes and in mice with obesity induced by HFD. The findings from the proposed studies will provide new mechanistic insights for targeting inflammasomes to develop novel therapeutic strategies for treatment and prevention of ESRD in obese patients.

Public Health Relevance

Obesity has become a major global health concern, and its incidence has increased sharply in recent years. The present grant proposal seeks to delineate the early initiating processes responsible for the kidney injury during obesity. We will study the role of a novel non-inflammatory mechanism, inflammasomes in obesity- induced renal injury which will importantly contribute to our understanding of the early mechanisms responsible for kidney damage during obesity and provide novel ideas for the nephrologists to develop new therapeutic strategies in prevention and treatment of end stage renal disease in obese patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rys-Sikora, Krystyna E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Houston
Schools of Pharmacy
United States
Zip Code
Wang, Zhengchao; Zhu, Qing; Wang, Weili et al. (2017) Infusion of Valproic Acid Into the Renal Medulla Activates Stem Cell Population and Attenuates Salt-Sensitive Hypertension in Dahl S Rats. Cell Physiol Biochem 42:1264-1273
Koka, Saisudha; Xia, Min; Chen, Yang et al. (2017) Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia. Redox Biol 13:336-344
Conley, Sabena M; Abais, Justine M; Boini, Krishna M et al. (2017) Inflammasome Activation in Chronic Glomerular Diseases. Curr Drug Targets 18:1019-1029
Boini, Krishna M; Xia, Min; Koka, Saisudha et al. (2017) Sphingolipids in obesity and related complications. Front Biosci (Landmark Ed) 22:96-116
Boini, Krishna M; Hussain, Tahir; Li, Pin-Lan et al. (2017) Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction. Cell Physiol Biochem 44:152-162
Zhu, Qing; Hu, Junping; Wang, Lei et al. (2017) Inhibition of microRNA-429 in the renal medulla increased salt sensitivity of blood pressure in Sprague Dawley rats. J Hypertens 35:1872-1880
Bao, Jun-Xiang; Zhang, Qin-Fang; Wang, Mi et al. (2017) Implication of CD38 gene in autophagic degradation of collagen I in mouse coronary arterial myocytes. Front Biosci (Landmark Ed) 22:558-569
Hu, Junping; Wang, Weili; Zhang, Fan et al. (2017) Hypoxia inducible factor-1? mediates the profibrotic effect of albumin in renal tubular cells. Sci Rep 7:15878
Conley, Sabena M; Abais-Battad, Justine M; Yuan, Xinxu et al. (2017) Contribution of guanine nucleotide exchange factor Vav2 to NLRP3 inflammasome activation in mouse podocytes during hyperhomocysteinemia. Free Radic Biol Med 106:236-244
Xia, Min; Abais, Justine M; Koka, Saisudha et al. (2016) Characterization and Activation of NLRP3 Inflammasomes in the Renal Medulla in Mice. Kidney Blood Press Res 41:208-21

Showing the most recent 10 out of 14 publications