美国德克萨斯大学Philipp E. Scherer小组发现，肾脏胰高血糖素受体对肾功能和全身稳态至关重要，其下调是导致慢性肾病的原因之一。这一研究成果于2024年1月17日在线发表在国际学术期刊《细胞—代谢》上。

研究人员发现，成年肾脏胰高血糖素受体（Gcgr）基因敲除小鼠表现出代谢失调和肾脏功能损害。这些小鼠表现出与肾脏葡萄糖输出量减少、氧化应激、炎性小体活性增强和肾脏脂质过度积累有关的高氨基酸血症。当受到脂质挑战时，它们会表现出急性高甘油三酯血症和慢性促炎症和组织坏死激活的不良反应。在老龄小鼠中，肾脏Gcgr去除会引起肾脏胶原蛋白和纤维连接蛋白的广泛沉积，表明肾脏纤维化。

综上所述，这些研究结果表明，肾脏GCGR在正常的肾脏代谢和平衡功能中起着至关重要的作用。重要的是，缺乏肾脏Gcgr的小鼠再现了慢性肾病的一些关键病理生理特征。

据了解，肾脏中的GCGR在肾小管中表达。在人类和慢性肾病动物模型中，肾脏GCGR的表达量减少。然而，肾脏GCGR在正常肾功能和疾病发展中的作用尚未得到研究。

附：英文原文

Title: Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease

Author: May-Yun Wang, Zhuzhen Zhang, Shangang Zhao, Toshiharu Onodera, Xue-Nan Sun, Qingzhang Zhu, Chao Li, Na Li, Shiuhwei Chen, Megan Paredes, Laurent Gautron, Maureen J. Charron, Denise K. Marciano, Ruth Gordillo, Daniel J. Drucker, Philipp E. Scherer

Issue&Volume: 2024-01-17

Abstract: The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humansand animal models with chronic kidney disease, renal GCGR expression is reduced. However,the role of kidney GCGR in normal renal function and in disease development has notbeen addressed. Here, we examined its role by analyzing mice with constitutive orconditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of thekidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucoseoutput, oxidative stress, enhanced inflammasome activity, and excess lipid accumulationin the kidney. Upon a lipid challenge, they display maladaptive responses with acutehypertriglyceridemia and chronic proinflammatory and profibrotic activation. In agedmice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicativeof fibrosis. Taken together, our findings demonstrate an essential role of the renalGCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficientfor kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease.

DOI: 10.1016/j.cmet.2023.12.024

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00475-8