Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Am J Physiol Cell Physiol. 2023 Jul 1;325(1):C243-C256. doi: 10.1152/ajpcell.00147.2023. Epub 2023 Jun 5.
Two novel treatments for diabetic kidney disease have emerged after decades with little progression. Both agents were developed for improved glycemic control in patients with type-2 diabetes. However, large clinical trials showed renoprotective effects beyond their ability to lower plasma glucose levels, body weight, and blood pressure. How this renal protection occurs is unknown. We will discuss their physiological effects, with special focus on the renal effects. We discuss how these drugs affect the function of the diabetic and nondiabetic kidneys to elucidate mechanisms by which the renoprotection could arise. Diabetic kidney disease affects the glomerular capillaries, which are usually protected by the renal autoregulatory mechanisms, the myogenic response, and the tubuloglomerular feedback mechanism. Animal models with reduced renal autoregulatory capacity develop chronic kidney disease. Despite different cellular targets, both drugs are suspected to affect renal hemodynamics through changes in the renal autoregulatory mechanisms. The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert a direct vasodilatory effect on the afferent arteriole (AA) positioned just before the glomerulus. Paradoxically, this effect is expected to increase glomerular capillary pressure, causing glomerular injury. In contrast, the sodium-glucose transporter-2 inhibitors (SGLT2i) are believed to activate the tubuloglomerular feedback mechanism to elicit vasoconstriction of the afferent arteriole. Because of their opposing effects on the renal afferent arterioles, it appears unlikely that their renoprotective effects can be explained by common effects of renal hemodynamics, but both drugs appear to add protection to the kidney beyond what can be obtained with classical treatment targeted at lowering blood glucose levels and blood pressure.
两种新型治疗糖尿病肾病的药物在经过几十年几乎没有进展后出现。这两种药物均是为改善 2 型糖尿病患者的血糖控制而开发的。然而，大型临床试验显示，它们除了降低血糖水平、体重和血压外，还有肾脏保护作用。这种肾脏保护作用的发生机制尚不清楚。我们将讨论它们的生理作用，特别关注肾脏的作用。我们讨论这些药物如何影响糖尿病和非糖尿病肾脏的功能，以阐明肾脏保护作用可能产生的机制。糖尿病肾病会影响肾小球毛细血管，这些毛细血管通常受到肾脏自身调节机制、肌源性反应和管球反馈机制的保护。肾脏自身调节能力降低的动物模型会发展为慢性肾脏病。尽管药物的细胞靶点不同，但这两种药物都被怀疑通过改变肾脏自身调节机制来影响肾脏的血液动力学。胰高血糖素样肽-1 受体激动剂 (GLP-1RA) 对位于肾小球前的入球小动脉 (AA) 具有直接的血管扩张作用。矛盾的是，这种作用预计会增加肾小球毛细血管压力，导致肾小球损伤。相比之下，钠-葡萄糖共转运蛋白-2 抑制剂 (SGLT2i) 被认为可以激活管球反馈机制，引起入球小动脉的血管收缩。由于它们对肾脏入球小动脉的作用相反，它们的肾脏保护作用似乎不太可能通过共同的肾脏血液动力学作用来解释，但这两种药物似乎都能在降低血糖水平和血压的经典治疗基础上为肾脏提供额外的保护。
