Obesity-associated renal alterations are mediated by Microsomal Prostaglandin E Synthase-1 (mPGES-1) in a sex-dependent manner.

Abstract

Introduction: Obesity is characterized by a chronic-low grade inflammation that causes pathophysiological alterations in different target organs, contributing, among others, to the development of renal damage. Microsomal Prostaglandin E Synthase 1 (mPGES-1) is an inducible isomerase responsible for the overexpression of prostaglandin E2 (PGE2) under inflammatory conditions, including obesity. Inhibition of PGE2 production by non-steroidal anti-inflammatory drugs, that block cyclooxygenase-2 (COX-2) cascade, limits inflammatory processes. However, it can be associated with side- effects as nephrotoxicity due to the inhibition of other prostaglandins production. New drugs targeting mPGES-1 have shown promising results in different experimental models. Nevertheless, to our knowledge, efficacy of inhibition downstream COXs in the renal impact of obesity remains unexplored. Objective: To elucidate whether mPGES-1 depletion could prevent the development of renal alterations in an experimental model of obesity. Methods: We have developed a model of HFD-induced obesity (60% fat, 13 weeks) in males and females mPGES-1-/- and their control littermates mPGES-1+/+ mice. Renal structural alterations and changes in mRNA expression were studied by histological analysis and q-RT-PCR, respectively. Results: IHFD decreased renal mPGES-1 gene expression in females but not in males. On the contrary, mPGES-1 expression was upregulated in perirenal adipose tissue (PRAT) of both sexes. In females, HFD induced kidney and PRAT hypertrophy that was prevented by the absence of mPGES-1; whereas in males, HFD did not modify kidney weight, while increasing PRAT weight significantly more in mPGES-1+/+ than in mPGES-1-/- mice. Rt-qPCR studies revealed that HFD induced renal damage, inflammation and fibrosis in mPGES-1+/+ male mice, which was not observed in mPGES-1 deficient mice. In agreement, histological studies showed that HFD induced glomerular hypertrophy and renal fibrosis only in mPGES-1+/+ HFD males. These alterations were not likely mediated by oxidative stress. Of note, females were protected against renal inflammatory and fibrotic alterations induced by HFD. Additionally, mPGES-1 deficiency prevented HFD- induced PRAT inflammation, fibrosis and hypoxia in both males and females. HFD did not modify serum proteinuria in any sex. Conclusion: mPGES-1 participates in the renal alterations associated with obesity in a s ex-dependent manner.