Upregulation of Nrf2 and Decreased Redox Signaling Contribute to Renoprotective Effects of Chemerin Receptor Blockade in Diabetic Mice.

Karla Bianca Neves,Augusto Cesar Montezano,Rafael Menezes Costa,Roberto S Costa,Thiago Bruder-Nascimento,Rita C Tostes,Rheure Alves-Lopes,Rhian M Touyz

doi:10.3390/ijms19082454

Karla Bianca Neves, Augusto Cesar Montezano + Show 6 more

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https://doi.org/10.3390/ijms19082454

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Abstract

Chemerin, acting through its receptor ChemR23, is an adipokine associated with inflammatory response, glucose and lipid metabolism and vascular function. Although this adipokine has been associated with the development and progression of kidney disease, it is not clear whether the chemerin/ChemR23 system plays a role in renal function in the context of diabetes. Therefore, we sought to determine whether ChemR23 receptor blockade prevents the development and/or progression of diabetic nephropathy and questioned the role of oxidative stress and Nrf2 in this process. Renal redox state and function were assessed in non-diabetic lean db/m and diabetic obese db/db mice treated with vehicle or CCX832 (ChemR23 antagonist). Renal reactive oxygen species (ROS) production, which was increased in diabetic mice, was attenuated by CCX832. This was associated with an increase in Nox 4 expression. Augmented protein oxidation in db/db mice was not observed when mice were treated with CCX832. CCX832 also abrogated impaired Nrf2 nuclear activity and associated downregulation in antioxidants expression in kidneys from db/db mice. Our in vivo findings highlight the role of the redox signaling and Nrf2 system as renoprotective players during chemerin receptor blockade in diabetic mice. The chemerin/ChemR23 system may be an important target to limit renal dysfunction associated with obesity-related diabetes.

Highlights

Chemerin, known as tazarotene-induced gene-2 protein or retinoic acid receptor responder protein-2 (RARRES2), is a 16 kDa protein predominantly secreted by adipose tissue and skin [1,2]
Chemerin is a ligand for the chemokine-like receptor 1 (CMKLR1; called ChemR23), a Gi protein-linked receptor mainly expressed by dendritic cells, macrophages, adipose tissue, vascular smooth muscle and endothelial cells, in addition to the chemokine receptor like 2 (CCRL2) and G-protein-coupled receptor 1 (GPR1) [6,7,8]
In db/db mice, which we previously phenotyped [37,38,39,40] we show that chemerin receptor antagonism by CCX832 did not significantly alter increased kidney mass (Figure 1A), but it decreased urinary creatinine levels (Figure 1B) and albuminuria (Figure 1C) in db/db diabetic mice, indicating that CCX832 prevents renal dysfunction observed in db/db mice

Summary

Introduction

Known as tazarotene-induced gene-2 protein or retinoic acid receptor responder protein-2 (RARRES2), is a 16 kDa protein predominantly secreted by adipose tissue and skin [1,2]. It has been associated with inflammatory response, glucose and lipid metabolism [3] and vascular function [4,5]. Enhanced expression of chemerin in white adipose tissue, skeletal muscle, and liver has been reported in db/db mice, an experimental model of obesity-related type 2 diabetes (T2D) where this adipokine exacerbates glucose intolerance, lowers serum insulin levels, and decreases tissue glucose uptake [16,17]

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