Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University Magdeburg, Magdeburg, Germany
Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
J Am Soc Nephrol. 2020 Aug;31(8):1762-1780. doi: 10.1681/ASN.2019111163. Epub 2020 Jul 24.
Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease-dependent signaling modulates dNP, in part the G protein-coupled, protease-activated receptors (PARs). Specifically, the cytoprotective protease-activated protein C (aPC) protects from dNP, but the mechanisms are not clear.
A combination of approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP.
The zymogen protein C and aPC bind to podocyte integrin-, a subunit of integrin-. Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin- induces transient binding of integrin- with G and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin- its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin-, aPC induces sustained RhoA activation, mimicking the effect of thrombin. , overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC-integrin- interaction by specifically deleting podocyte integrin- or by abolishing aPC's integrin-binding RGD sequence enhances RhoA signaling in mice with high aPC levels and abolishes aPC's nephroprotective effect. Pharmacologic inhibition of PAR1, the pivotal thrombin receptor, restricts RhoA activation and nephroprotects RGE-aPC and wild-type mice. aPC-integrin- acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin- as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.
糖尿病肾病（dNP）是目前导致终末期肾病（ESKD）的主要原因，但其缺乏有效的治疗方法。凝血蛋白酶依赖性信号转导调节 dNP，部分是通过 G 蛋白偶联蛋白酶激活受体（PARs）。具体而言，细胞保护蛋白酶激活蛋白 C（aPC）可防止 dNP，但机制尚不清楚。
采用多种方法和小鼠模型，评估了 aPC-整合素相互作用及其相关信号在 dNP 中的作用。
酶原蛋白 C 和 aPC 与足细胞整合素-α 亚基结合，整合素-α 亚基是整合素的一部分。该整合素的缺失会损害凝血酶介导的足细胞中 aPC 的生成。aPC 与整合素-α 的相互作用诱导整合素-α 与 G 蛋白的瞬时结合，并控制足细胞中 PAR 依赖的 RhoA 信号转导。aPC 与整合素-α 的结合及其 RGD 序列是限制 RhoA 信号转导在足细胞中的时间限制所必需的。在缺乏整合素-α 的足细胞中，aPC 诱导 RhoA 的持续激活，模拟凝血酶的作用。此外，野生型 aPC 的过表达可抑制病理性肾 RhoA 激活并预防 dNP。通过特异性敲除足细胞整合素-α 或消除 aPC 的整合素结合 RGD 序列来破坏 aPC-整合素-α 相互作用，可增强高 aPC 水平小鼠的 RhoA 信号转导，并消除 aPC 的肾保护作用。PAR1 的药理学抑制，即关键的凝血酶受体，可限制 RhoA 激活并保护 RGE-aPC 和野生型小鼠免受肾损伤。aPC-整合素-α 作为变阻器，在糖尿病肾病中控制足细胞中 PAR1 依赖性 RhoA 激活。这些结果表明，整合素-α 是 aPC 的必需核心受体，对于 aPC 在 dNP 中的 PAR 信号转导具有肾保护作用。
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