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High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease.

Publication ,  Journal Article
Alhasson, F; Seth, RK; Sarkar, S; Kimono, DA; Albadrani, MS; Dattaroy, D; Chandrashekaran, V; Scott, GI; Raychoudhury, S; Nagarkatti, M ...
Published in: Redox Biol
July 2018

High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21. High-fat diet (60% kcal) was used to induce fatty liver phenotype with parallel insulin and leptin resistance. The kidneys were probed for mesangial cell activation and tubular inflammation that showed accelerated NASH phenotype and oxidative stress in the liver. Results showed that NAFLD kidneys had significant increases in α-SMA, a marker of mesangial cell activation, miR21 levels, tyrosine nitration and renal inflammation while they were significantly decreased in leptin and p47 phox knockout mice. Micro RNA21 knockout mice showed decreased tubular immunotoxicity and proinflammatory mediator release. Mechanistically, use of NOX2 siRNA or apocynin,phenyl boronic acid (FBA), DMPO or miR21 antagomir inhibited leptin primed-miR21-mediated mesangial cell activation in vitro suggesting a direct role of leptin-mediated NOX-2 in miR21-mediated mesangial cell activation. Finally, JAK-STAT inhibitor completely abrogated the mesangial cell activation in leptin-primed cells suggesting that leptin signaling in the mesangial cells depended on the JAK-STAT pathway. Taken together the study reports a novel mechanistic pathway of leptin-mediated renal inflammation that is dependent on NOX-2-miR21 axis in ectopic manifestations underlying NAFLD-induced co-morbidities.

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Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

July 2018

Volume

17

Start / End Page

1 / 15

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • STAT Transcription Factors
  • Peroxynitrous Acid
  • Oxidative Stress
  • Non-alcoholic Fatty Liver Disease
  • NADPH Oxidase 2
  • MicroRNAs
  • Mice, Knockout
  • Mice
  • Mesangial Cells
 

Citation

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Alhasson, F., Seth, R. K., Sarkar, S., Kimono, D. A., Albadrani, M. S., Dattaroy, D., … Chatterjee, S. (2018). High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol, 17, 1–15. https://doi.org/10.1016/j.redox.2018.04.002
Alhasson, Firas, Ratanesh Kumar Seth, Sutapa Sarkar, Diana A. Kimono, Muayad S. Albadrani, Diptadip Dattaroy, Varun Chandrashekaran, et al. “High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease.Redox Biol 17 (July 2018): 1–15. https://doi.org/10.1016/j.redox.2018.04.002.
Alhasson, Firas, et al. “High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease.Redox Biol, vol. 17, July 2018, pp. 1–15. Pubmed, doi:10.1016/j.redox.2018.04.002.
Alhasson F, Seth RK, Sarkar S, Kimono DA, Albadrani MS, Dattaroy D, Chandrashekaran V, Scott GI, Raychoudhury S, Nagarkatti M, Nagarkatti P, Diehl AM, Chatterjee S. High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol. 2018 Jul;17:1–15.
Journal cover image

Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

July 2018

Volume

17

Start / End Page

1 / 15

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • STAT Transcription Factors
  • Peroxynitrous Acid
  • Oxidative Stress
  • Non-alcoholic Fatty Liver Disease
  • NADPH Oxidase 2
  • MicroRNAs
  • Mice, Knockout
  • Mice
  • Mesangial Cells