The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and 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 not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the . Adult renal knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney recapitulate some of the key pathophysiological features of chronic kidney disease.

中文翻译：

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肾脏胰高血糖素受体的下调对肾功能和全身稳态至关重要，会导致慢性肾脏疾病

肾脏中的胰高血糖素受体（GCGR）在肾单位小管中表达。在患有慢性肾病的人类和动物模型中，肾脏 GCGR 表达降低。然而，肾脏 GCGR 在正常肾功能和疾病发展中的作用尚未得到解决。在这里，我们通过分析具有组成性或条件性肾脏特异性缺失的小鼠来检查其作用。成年肾基因敲除小鼠表现出代谢失调和肾脏功能损伤。这些小鼠表现出与肾脏葡萄糖输出减少、氧化应激、炎性体活性增强和肾脏中过量脂质积累相关的高氨基酸血症。在脂质挑战后，它们表现出适应不良反应，伴有急性高甘油三酯血症和慢性促炎和促纤维化激活。在老年小鼠中，肾脏消融引起胶原和纤连蛋白在肾脏广泛沉积，表明纤维化。综上所述，我们的研究结果证明了肾脏 GCGR 在正常肾脏代谢和稳态功能中的重要作用。重要的是，肾缺陷小鼠重现了慢性肾病的一些关键病理生理学特征。