Hyperglycemia induces NF‐κB activation and MCP‐1 expression via downregulating GLP‐1R expression in rat mesangial cells: inhibition by metformin

Abstract

Hyperglycemia impairs glucagon‐like peptide‐1 receptor (GLP‐1R) signaling in multiple cell types and thereby potentially attenuates the therapeutic effects of GLP‐1R agonists. We hypothesized that the downregulation of GLP‐1R by hyperglycemia might reduce the renal‐protective effects of GLP‐1R agonists in diabetic nephropathy (DN). In this study, we examined the effects of high glucose on the expression of GLP‐1R and its signaling pathways in the HBZY‐1 rat mesangial cell line. We found that high glucose reduced GLP‐1R messenger RNA (mRNA) levels in HBZY‐1 cells and in the renal cortex in db/db mice comparing with control groups. In consistence, GLP‐1R agonist exendin‐4 induced CREB phosphorylation was attenuated by high glucose but not low glucose treatment, which is paralleled with abrogated anti‐inflammatory functions in HBZY‐1 cells linked with nuclear factor‐κB (NF‐κB) activation. In consistence, GLP‐1R inhibition aggravated the high glucose‐induced activation of NF‐κB and MCP‐1 protein levels in cultured HBZY‐1 cells while overexpression of GLP‐1R opposite effects. We further proved that metformin restored high glucose‐inhibited GLP‐1R mRNA expression and decreased high glucose evoked inflammation in HBZY‐1 cells. On the basis of these findings, we conclude that high glucose lowers GLP‐1R expression and leads to inflammatory responses in mesangial cells, which can be reversed by metformin. These data support the rationale of combinative therapy of metformin with GLP‐1R agonists in DN.

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…GLP-1 receptor agonists (GLP-1 RA) are used in the metabolic control of obesity and T2DM patients because they enhance glucose-dependent insulin synthesis and secretion, proliferation of β-cells, inhibition of β-cells apoptosis, delay of gastric emptying and regulation of appetite by satiety-effects with body weight reduction [323][324][325]. GLP-1 RA reduces albuminuria and histological renal damage [326], and downregulates genes related to inflammation (NF-κB, TNF-α, MCP-1) [327], oxidative stress (Nox4 and subunits gp91phox, p22phox, p47phox) [328], de novo lipogenesis/lipotoxicity (SREBP-1; ABCA1) [329] and fibrosis (α-SMA, fibronectin, collagen I) [330]. These renoprotective effects observed in T2DM and CKD patients have been validated by four major clinical trials AWARD-7 [331], LEADER [332], SUSTAIN-6 [333] and ELIXA [334].…”

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

“…NF-κB plays a central role in the inflammatory pathway in the development of DKD ( Kawanami et al., 2016 ). The hyperglycemia-induced downregulation of GLP-1R is involved in NF-κB activation and the subsequent inflammatory response in mesangial cells ( Kang et al., 2019 ). Liraglutide has been shown to increase renal endothelial nitric oxide synthase (eNOS) levels by downregulating NF-κB in STZ-induced diabetic rats ( Zhou et al., 2014 ).…”

Accelerated Kidney Aging in Diabetes Mellitus

“…Additionally, metformin adjusted nephrin protein expression [180] and repressed oxidative injury to restore podocytes [181] and also relieved insulin resistance of podocytes through activating Sirt1 and AMPK in diabetic rats [182]. Metformin alleviated inflammation of mesangial cells [183], which was related to upregulated glucagon-like peptide-1 (GLP-1) receptor expression [184]. The Sirt1/Foxo1 signal pathway was focused on demonstrating the antioxidative stress effect of metformin subsequently with the activation of autophagy in diabetic rats and high-glucose-induced mesangial cells [185,186].…”