Role of vascular smooth muscle GLP-1 receptor signaling in diabetic kidney fibrosis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08582
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Akita University
• Principal Investigator: Fujita Hiroki 秋田大学, 医学系研究科, 准教授 (30333933)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 糖尿病性腎症 / GLP-1受容体シグナル / 血管平滑筋 / 腎線維化 / Akita糖尿病マウスモデル

Outline of Final Research Achievements

C57BL/6-Akita mice are known to be resistant to the development of diabetic nephropathy. We generated vascular smooth muscle GLP-1 receptor-deficient C57BL/6-Akita mice and investigated their renal phenotypes. Reduction in vascular smooth muscle GLP-1 receptor signaling increased renal oxidative stress via diminished antioxidant defense capacity in renal vascular wall, and accelerated diabetic glomerulosclerosis, renal interstitial fibrosis, structural injury in proximal tubular mitochondria, and renal vascular wall thickening. In addition, vascular smooth muscle GLP-1 receptor-deficient C57BL/6-Akita mice developed moderate albuminuria and exhibited blood pressure elevation, possibly due to reduced nitric oxide levels in renal glomerular and vascular endothelial cells. These findings indicate that vascular smooth muscle GLP-1 receptor signaling exerts renal protective effects in diabetic nephropathy.

Free Research Field

腎臓病学、糖尿病学

Academic Significance and Societal Importance of the Research Achievements

血管平滑筋GLP-1受容体シグナルは慢性の高血糖状態下で惹起される酸化ストレスを減少させることで、糖尿病性糸球体硬化病変、腎間質線維化、腎臓内血管壁硬化性変化の進行抑制に寄与することが本研究の成果から明らかとなった。したがって、血管平滑筋GLP-1受容体シグナルを高める介入は糖尿病性腎症のみならず、他の慢性腎臓病の血管病変に対する新規治療戦略として期待されるところである。しかしながら、血管平滑筋GLP-1受容体シグナルの腎保護効果の基盤となる詳細な分子メカニズムについては未だ解明の余地があり、今後のさらなる研究の遂行が必要である。