Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγ
Fei Wang, Renfei Luo, Chang-Jiang Zou, Shiying Xie, Kexin Peng, Long Zhao, Kevin T. Yang, Chuanming Xu, Tianxin Yang
Fei Wang, Renfei Luo, Chang-Jiang Zou, Shiying Xie, Kexin Peng, Long Zhao, Kevin T. Yang, Chuanming Xu, Tianxin Yang
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Research Article Metabolism

Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγ

Abstract

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention. Conversely, inhibition of endogenous sPRR production by PF429242 induced diabetes and insulin resistance, both of which were reversed by the sPRR-His supplement. At the cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of glucose transporter 4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes and insulin resistance associated with reduced adipose PRR expression and circulating sPRR. The sPRR-His supplement in the null mice nearly normalized blood glucose and insulin levels. Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exhibits a therapeutic potential in management of metabolic syndrome via interaction with PPARγ.

Authors

Fei Wang, Renfei Luo, Chang-Jiang Zou, Shiying Xie, Kexin Peng, Long Zhao, Kevin T. Yang, Chuanming Xu, Tianxin Yang

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Figure 9

Definition of PRR as a direct target gene of PPARγ and in differentiated 3T3 cells.

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Definition of PRR as a direct target gene of PPARγ and in differentiated...
(A) Schematic illustration of the mutagenesis of the 2 PPRE sites in the promoter of PRR. (B) Luciferase assay for PRR promoter activity. The 3T3 cells were transfected with empty vector or vectors carrying a 2-kb flanking region of the promoter with or without mutagenesis of either one of the PRRE sites (n = 5, repeat 2 times). (C) The effect of rosiglitazone (Rosi) on PRR protein expression (n = 4, repeat 3 times). The cells were treated for 24 hours with vehicle or Rosi, followed by immunoblotting analysis of PRR. The same samples were run on a separate gel for detecting GAPDH. The densitometry values are shown underneath the blots. (D) The effect of Rosi on sPRR production. The cells were treated for 24 hours with vehicle, PF, Rosi, or Rosi + PF, followed by ELISA measurement of medium sPRR (n = 10). (E) The role of sPRR in mediating Rosi-induced insulin sensitivity (n = 10). The cells were treated for 24 hours with vehicle, Rosi, Rosi + PF, Rosi + PF + sPRR-His, or Rosi + sPRR ab, and then each group was divided to receive vehicle or 20-minute insulin treatment, followed by the assay for glucose uptake. *P < 0.05 vs. vehicle (C). Statistical significance was determined by using ANOVA with the Bonferroni test. Data are shown as mean ± SEM. P-Luc, PRR promoter-luciferase constructor; Δ-P-Luc, PPRE mutation of PRR promoter-luciferase construction; sPRR ab, sPRR antibody.