Department of Nephrology, Medical School Duesseldorf, Heinrich Heine University, Duesseldorf, Germany.
FASEB J. 2024 Sep 15;38(17):e70018. doi: 10.1096/fj.202400369R.
Albuminuria is characterized by a disruption of the glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane, and the slit diaphragm. Nephrin is a major component of the slit diaphragm. Apart from hemodynamic effects, Ang II enhances albuminuria by β-Arrestin2-mediated nephrin endocytosis. Blocking the AT1 receptor with candesartan and irbesartan reduces the Ang II-mediated nephrin-β-Arrestin2 interaction. The inhibition of MAPK ERK 1/2 blocks Ang II-enhanced nephrin-β-Arrestin2 binding. ERK 1/2 signaling, which follows AT1 receptor activation, is mediated by G-protein signaling, EGFR transactivation, and β-Arrestin2 recruitment. A mutant AT1 receptor defective in EGFR transactivation and β-Arrestin2 recruitment reduces the Ang II-mediated increase in nephrin β-Arrestin2 binding. The mutation of β-Arrestin2, critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. β-Arrestin2 does not influence nephrin cell surface expression. The data presented here deepen our molecular understanding of a blood-pressure-independent molecular mechanism of AT-1 receptor blockers (ARBs) in reducing albuminuria.
蛋白尿的特征是肾小球滤过屏障的破坏，该屏障由有孔的内皮细胞、肾小球基底膜和裂孔隔膜组成。nephrin 是裂孔隔膜的主要组成部分。除了血流动力学效应外，Ang II 通过β-Arrestin2 介导的nephrin 内吞作用增强蛋白尿。用坎地沙坦和厄贝沙坦阻断 AT1 受体减少 Ang II 介导的 nephrin-β-Arrestin2 相互作用。MAPK ERK 1/2 的抑制阻断了 Ang II 增强的 nephrin-β-Arrestin2 结合。ERK 1/2 信号转导紧随 AT1 受体激活，由 G 蛋白信号转导、EGFR 反式激活和β-Arrestin2 募集介导。一种在 EGFR 反式激活和β-Arrestin2 募集中缺陷的突变 AT1 受体减少 Ang II 介导的 nephrin β-Arrestin2 结合增加。β-Arrestin2 突变，对 AT1 受体结合至关重要，完全阻断了与 nephrin 的相互作用，与 Ang II 刺激无关。β-Arrestin2 不影响 nephrin 的细胞表面表达。这里呈现的数据加深了我们对 AT1 受体阻滞剂 (ARB) 降低蛋白尿的一种血压非依赖性分子机制的分子理解。
