Oncotarget

Research Papers:

Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: role of acid sphingomyelinase gene

Krishna M. Boini _, Min Xia, Saisudha Koka, Todd w. Gehr and Pin-Lan Li

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Oncotarget. 2016; 7:19031-19044. https://doi.org/10.18632/oncotarget.8023

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Abstract

Krishna M. Boini1,2, Min Xia1, Saisudha Koka1, Todd W. Gehr2 and Pin-Lan Li1

1Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond VA 23298, USA

2Division of Nephrology, School of Medicine, Virginia Commonwealth University, Richmond VA 23298, USA

Correspondence to:

Krishna M. Boini, e-mail: kmboini@vcu.edu

Keywords: obesity, inflammasomes, ceramide, glomerulosclerosis, end-stage renal disease

Received: December 30, 2015     Accepted: January 29, 2016     Published: March 10, 2016

ABSTRACT

Ceramide has been reported to initiate inflammasome formation and activation in obesity and different pathological conditions. The present study was performed to explore the role of acid sphingomyelinase (Asm) in the development of high fat diet (HFD)-induced inflammasome and activation and consequent glomerular injury. Asm knockout (Asm-/-) and wild type (Asm+/+) mice with or without Asm short hairpin RNA (shRNA) transfection were fed a HFD or normal chow for 12 weeks to produce obesity and associated glomerular injury. HFD significantly enhanced the Asm activity, ceramide production, colocalization of Nlrp3 (Nod-like receptor protein 3) with ASC (apoptosis-associated speck-like protein) or Caspase-1, NADPH-dependent superoxide (O2•−) production in glomeruli of Asm+/+mice than in control diet-fed mice. However, such HFD-induced increases in Asm activity, ceramide production, colocalization of Nlrp3 with ASC or Caspase-1, superoxide (O2•−) production was attenuated in Asm-/- or Asm shRNA-transfected wild-type mice. In consistency with decreased inflammasome formation, the caspase-1 activity and IL-1β production was significantly attenuated in Asm-/- or Asm shRNA-transfected wild-type mice fed a HFD. Morphological examinations showed that HFD-induced profound injury in glomeruli of Asm+/+ mice which was markedly attenuated in Asm-/- mice. The decreased glomerular damage index in Asm-/- mice was accompanied by attenuated proteinuria. Fluorescent immunohistochemical examinations using podocin as a podocyte marker showed that inflammasome formation induced by the HFD were mostly located in podocytes as demonstrated by co-localization of podocin with Nlrp3. In conclusion, these observations disclose a pivotal role of Asm in the HFD-induced inflammasome formation and consequent glomerular inflammation and injury.


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