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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.

ABSTRACT: 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 ?-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.

SUBMITTER: Alhasson F

PROVIDER: S-EPMC6006523 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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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.

Alhasson Firas F Seth Ratanesh Kumar RK Sarkar Sutapa S Kimono Diana A DA Albadrani Muayad S MS Dattaroy Diptadip D Chandrashekaran Varun V Scott Geoffrey I GI Raychoudhury Samir S Nagarkatti Mitzi M Nagarkatti Prakash P Diehl Anna Mae AM Chatterjee Saurabh S

Redox biology 20180407

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 ...[more]

PMID: 29660503

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Project description:Interaction of transforming growth factor-β (TGFβ)-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of the TGFβ receptor involved in the noncanonical signaling is unknown. Here, we show that TGFβ increased the catalytic loop phosphorylation of platelet-derived growth factor receptor β (PDGFRβ), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFβ increased phosphorylation of the PI 3-kinase-interacting Tyr-751 residue of PDGFRβ, thus activating Akt. Inhibition of PDGFRβ using a pharmacological inhibitor and siRNAs blocked TGFβ-stimulated phosphorylation of proline-rich Akt substrate of 40 kDa (PRAS40), an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active myristoylated Akt reversed the siPDGFRβ-mediated inhibition of mTORC1 activity; however, co-expression of the phospho-deficient mutant of PRAS40 inhibited the effect of myristoylated Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRβ in mesangial cells. Additionally, we demonstrate that PDGFRβ-initiated phosphorylation of PRAS40 is required for TGFβ-induced mesangial cell hypertrophy and fibronectin and collagen I (α2) production. Increased activating phosphorylation of PDGFRβ is also associated with enhanced TGFβ expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rats, respectively. Thus, pursuing TGFβ noncanonical signaling, we identified how TGFβ receptor I achieves mTORC1 activation through PDGFRβ-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRβ in TGFβ-driven renal fibrosis.

Project description:Nonalcoholic fatty liver disease (NAFLD) is an emerging global pandemic. Though significant progress has been made in unraveling the pathophysiology of the disease, the role of protein phosphatase 2A (PP2A) and its subsequent inhibition by environmental and genetic factors in NAFLD pathophysiology remains unclear. The present report tests the hypothesis that an exogenous PP2A inhibitor leads to hepatic inflammation and fibrogenesis via an NADPH oxidase 2 (NOX2)-dependent pathway in NAFLD. Results showed that microcystin (MC) administration, a potent PP2A inhibitor found in environmental exposure, led to an exacerbation of NAFLD pathology with increased CD68 immunoreactivity, the release of proinflammatory cytokines, and stellate cell activation, a process that was attenuated in mice that lacked the p47phox gene and miR21 knockout mice. Mechanistically, leptin-primed immortalized Kupffer cells (a mimicked model for an NAFLD condition) treated with apocynin or nitrone spin trap 5,5 dimethyl-1- pyrroline N-oxide (DMPO) had significantly decreased CD68 and decreased miR21 and ?-smooth muscle actin levels, suggesting the role of NOX2-dependent reactive oxygen species in miR21-induced Kupffer cell activation and stellate cell pathology. Furthermore, NOX2-dependent peroxynitrite generation was primarily responsible for cellular events observed following MC exposure since incubation with phenylboronic acid attenuated miR21 levels, Kupffer cell activation, and inflammatory cytokine release. Furthermore, blocking of the AKT pathway attenuated PP2A inhibitor-induced NOX2 activation and miR21 upregulation. Taken together, we show that PP2A may have protective roles, and its inhibition exacerbates NAFLD pathology via activating NOX2-dependent peroxynitrite generation, thus increasing miR21-induced pathology.NEW & NOTEWORTHY Protein phosphatase 2A inhibition causes nonalcoholic steatohepatitis (NASH) progression via NADPH oxidase 2. In addition to a novel emchanism of action, we describe a new tool to describe NASH histopathology.

Dataset Information

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

Publications

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

Similar Datasets

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