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 8

The role of S1P-derived sPRR on insulin signaling in differentiated 3T3 cells.

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The role of S1P-derived sPRR on insulin signaling in differentiated 3T3 ...
The cells were pretreated for 24 hours with vehicle, sPRR-His, PF, or PF + sPRR-His and treated for 20 minutes with vehicle or insulin, followed by measurement of glucose uptake and examination of p-AKT/AKT and Glut4 protein abundances. (A) Glucose uptake (n = 6, repeated for 3 times). (B) Immunoblotting analysis of p-AKT, AKT, and Glut4 in the whole cell lysates of the cells in A exposed to vehicle or sPRR-His for 24 hours (n = 3, repeated for 3 times). The blot was stripped and reprobed with anti-AKT antibody. The same protein samples were run on a separate gel for detecting GAPDH. (C and D) Immunoblotting analysis of the effect of sPRR-His on insulin-induced activation of p-AKT and Glut4 (n = 5, repeated for 2 times). The blot was stripped and reprobed with anti-AKT antibody or anti-Calnexin2 antibody. The cells were pretreated for 24 hours with vehicle or sPRR-His and then treated for 20 minutes with insulin, followed by immunoblotting analysis of p-AKT, AKT, and Glut4. (E) Effect of short-term sPRR-His treatment on basal and insulin-induced glucose uptake (n = 10). (F) ELISA measurement of medium sPRR in cells treated with vehicle or insulin for 20 minutes (n = 10). (G) Effect of PRR-neutralizing antibody on insulin-induced glucose uptake (n = 10). The cells were pretreated for 1 hour with vehicle or antibody and then treated with insulin for 20 minutes, followed by measurement of glucose uptake. *P < 0.05 vs. vehicle/CTR group in A or vehicle group in B–D, #P < 0.05 vs. vehicle/insulin group in A or insulin group in C and D. Statistical significance was determined by using ANOVA with the Bonferroni test for multiple comparisons. Data are shown as mean ± SEM.