Attenuation of diabetic kidney injury in DPP4-deficient rats; role of GLP-1 on the suppression of AGE formation by inducing glyoxalase 1
- Authors
- Sarker, Mithun Kumer; Lee, Jong Han; Lee, Dae Ho; Chun, Kwang-Hoon; Jun, Hee-Sook
- Issue Date
- 15-Jan-2020
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- diabetic nephropathy; dipeptidyl peptidase 4; glucagon-like peptide-1; glyoxalase-1; advanced glycation end products
- Citation
- AGING-US, v.12, no.1, pp.593 - 610
- Journal Title
- AGING-US
- Volume
- 12
- Number
- 1
- Start Page
- 593
- End Page
- 610
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/17632
- DOI
- 10.18632/aging.102643
- ISSN
- 1945-4589
- 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.
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