Abstract
Dipeptidyl peptidase 4 (DPP4) inactivates incretin hormone glucagon-like peptide-1. DPP4 inhibitors may exert beneficial effects on diabetic nephropathy (DN) independently of glycemic control; however, the mechanisms underlying are not fully understood. Here, we investigated the mechanisms of the beneficial effects of DPP4 inhibition on DN using DPP4-deficient (DPP4-def) rats and rat mesangial cells.Blood glucose and HbA1c significantly increased by streptozotocin (STZ) and no differences were between WT-STZ and DPP4-def-STZ. The albumin level in urine decreased significantly and the albumin/creatinine ratio decreased slightly in DPP4-def-STZ. The glomerular volume in DPP4-def-STZ significantly decreased compared with that of WT-STZ. Advanced glycation end products formation, receptor for AGE (RAGE) protein expression, and its downstream inflammatory cytokines and fibrotic factors in kidney tissue, were significantly suppressed in the DPP4-def-STZ compared to the WT-STZ with increasing glyoxalase-1 (GLO-1) expression responsible for the detoxification of methylglyoxal (MGO). In vitro, exendin-4 suppressed MGO-induced AGEs production by enhancing the expression of GLO-1 and nuclear factor-erythroid 2 p45 subunit-related factor 2, resulting in decreasing pro-inflammatory cytokine levels. This effect was abolished by GLO-1 siRNA.Our data suggest that endogenously increased GLP-1 in DPP4-deficient rats contributes to the attenuation of DN partially by regulating AGEs formation via upregulation of GLO-1 expression.
Highlights
The prevalence of diabetes is increasing worldwide, resulting in a dramatic increase in diabetic complications
Blood glucose and hemoglobin A1c (HbA1c) levels were significantly increased in wild type (WT)-STZ diabetic rats and there were no differences between WT and Dipeptidyl peptidase 4 (DPP4) deficient rats (Figure 1A, 1B)
To examine whether there is a change in the expression of inflammatory factors and fibrotic factors in the kidney of DPP4-deficient diabetic rats, we evaluated the expression of tumor necrosis factor (TNF)-α, interleukin (IL6), and monocyte chemoattractant protein (MCP)-1 as inflammatory cytokines, and transforming growth factor (TGF)-β and fibronectin (FN) as fibrotic factors
Summary
The prevalence of diabetes is increasing worldwide, resulting in a dramatic increase in diabetic complications. Diabetic nephropathy (DN) is a complication of diabetes, and around 40% patients with diabetes develop DN [1]. MGO is considered a main endogenous precursor for advanced glycation end products (AGEs) [4]. MGO is elevated in patients with diabetes and those with renal failure [5, 6]. Numerous studies have demonstrated that interactions between AGEs and their receptor (RAGE) evoke oxidative stress and the expression of inflammatory cytokines and fibrotic factors, leading to alterations in the renal structure and loss of renal function in diabetes www.aging-us.com [7,8,9]. RAGE knockout mice were resistant to the development of DN induced by streptozotocin (STZ) [10], suggesting that suppression of the AGE-RAGE axis in the kidneys might be a potential therapeutic target for treatment of DN
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