Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
Am J Physiol Renal Physiol. 2012 Apr 15;302(8):F986-97. doi: 10.1152/ajprenal.00595.2011. Epub 2012 Jan 11.
Although Smad3 is a key mediator for fibrosis, its functional role and mechanisms in hypertensive nephropathy remain largely unclear. This was examined in the present study in a mouse model of hypertension induced in Smad3 knockout (KO) and wild-type (WT) mice by subcutaneous angiotensin II infusion and in vitro in mesangial cells lacking Smad3. After angiotensin II infusion, both Smad3 KO and WT mice developed equally high levels of blood pressure. However, disruption of Smad3 prevented angiotensin II-induced kidney injury by lowering albuminuria and serum creatinine (P < 0.01), inhibiting renal fibrosis such as collagen type I and IV, fibronectin, and α-SMA expression (all P < 0.01), and blocking renal inflammation including macrophage and T cell infiltration and upregulation of IL-1β, TNF-α, and monocyte chemoattractant protein-1 in vivo and in vitro (all P < 0.001). Further studies revealed that blockade of angiotensin II-induced renal transforming growth factor (TGF)-β1 expression and inhibition of Smurf2-mediated degradation of renal Smad7 are mechanisms by which Smad3 KO mice were protected from angiotensin II-induced renal fibrosis and NF-κB-driven renal inflammation in vivo and in vitro. In conclusion, Smad3 is a key mediator of hypertensive nephropathy. Smad3 promotes Smurf2-dependent ubiquitin degradation of renal Smad7, thereby enhancing angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Results from this study suggest that inhibition of Smad3 or overexpression of Smad7 may be a novel therapeutic strategy for hypertensive nephropathy.
尽管 Smad3 是纤维化的关键介质，但它在高血压肾病中的功能作用和机制在很大程度上仍不清楚。本研究在 Smad3 敲除（KO）和野生型（WT）小鼠的高血压模型中通过皮下血管紧张素 II 输注以及在缺乏 Smad3 的系膜细胞中进行了研究。血管紧张素 II 输注后，Smad3 KO 和 WT 小鼠的血压均升高到相同水平。然而，Smad3 的破坏通过降低蛋白尿和血清肌酐（P<0.01）、抑制胶原 I 和 IV、纤连蛋白和α-SMA 表达等肾纤维化（均 P<0.01），以及阻断肾炎症包括巨噬细胞和 T 细胞浸润和体内和体外白细胞介素 1β、肿瘤坏死因子-α 和单核细胞趋化蛋白-1 的上调，预防了血管紧张素 II 诱导的肾脏损伤（均 P<0.001）。进一步的研究表明，阻断血管紧张素 II 诱导的肾脏转化生长因子（TGF）-β1 表达和抑制 Smad7 的 Smurf2 介导的降解是 Smad3 KO 小鼠免受血管紧张素 II 诱导的肾纤维化和 NF-κB 驱动的肾炎症的机制在体内和体外。总之，Smad3 是高血压肾病的关键介质。Smad3 促进 Smurf2 依赖性肾脏 Smad7 的泛素降解，从而增强血管紧张素 II 诱导的 TGF-β/Smad3 介导的肾纤维化和 NF-κB 驱动的肾炎症。本研究结果表明，抑制 Smad3 或过表达 Smad7 可能是高血压肾病的一种新的治疗策略。
