Department of Veterans Affairs, Nashville, TN
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Diabetes. 2020 Nov;69(11):2446-2457. doi: 10.2337/db20-0579. Epub 2020 Aug 25.
An increasing number of studies suggest that the renal proximal tubule is a site of injury in diabetic nephropathy (DN), and progressive renal tubulointerstitial fibrosis is an important mediator of progressive kidney dysfunction in DN. In this study, we observed increased expression and activation of YAP (yes-associated protein) in renal proximal tubule epithelial cells (RPTC) in patients with diabetes and in mouse kidneys. Inducible deletion of specifically in RPTC or administration of the YAP inhibitor verteporfin significantly attenuated diabetic tubulointerstitial fibrosis. EGFR-dependent activation of RhoA/Rock and PI3K-Akt signals and their reciprocal interaction were upstream of proximal tubule YAP activation in diabetic kidneys. Production and release of CTGF in culture medium were significantly augmented in human embryonic kidney (HEK)-293 cells transfected with a constitutively active YAP mutant, and the conditioned medium collected from these cells activated and transduced fibroblasts into myofibroblasts. This study demonstrates that proximal tubule YAP-dependent paracrine mechanisms play an important role in diabetic interstitial fibrogenesis; therefore, targeting Hippo signaling may be a therapeutic strategy to prevent the development and progression of diabetic interstitial fibrogenesis.
越来越多的研究表明，肾脏近端小管是糖尿病肾病（DN）损伤的部位，进行性肾小管间质纤维化是 DN 进行性肾功能障碍的重要介导者。在这项研究中，我们观察到糖尿病患者和小鼠肾脏中肾脏近端小管上皮细胞（RPTC）中 YAP（yes-associated protein）的表达和激活增加。特异性在 RPTC 中诱导缺失或给予 YAP 抑制剂 verteporfin 可显著减轻糖尿病肾小管间质纤维化。EGFR 依赖性 RhoA/Rock 和 PI3K-Akt 信号的激活及其相互作用是糖尿病肾脏中近端小管 YAP 激活的上游事件。在转染组成性激活的 YAP 突变体的人胚肾（HEK）-293 细胞中，细胞培养基中 CTGF 的产生和释放显著增加，并且从这些细胞收集的条件培养基激活并将成纤维细胞转导为肌成纤维细胞。这项研究表明，近端小管 YAP 依赖性旁分泌机制在糖尿病间质纤维化中起重要作用；因此，靶向 Hippo 信号可能是预防糖尿病间质纤维化发生和进展的治疗策略。
