Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kidney Int. 2017 May;91(5):1115-1125. doi: 10.1016/j.kint.2016.10.035. Epub 2017 Jan 10.
Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension-resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel α-subunit and tumor necrosis factor-α was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease.
血管紧张素 II 型 1 型受体相关蛋白（ATRAP）促进 AT1R 内化，并抑制组织 AT1R 信号的过度激活。在这里，我们提供的证据表明，肾 ATRAP 在慢性肾脏病的小鼠残余肾模型中抑制高血压中起关键作用。在 C57BL/6 和 129/Sv 小鼠的肾脏中检查了 5/6 肾切除术对内源性 ATRAP 表达的影响。虽然 129/Sv 小鼠残余肾显示肾 ATRAP 表达减少并发生高血压，但 C57BL/6 小鼠表现出增加的肾 ATRAP 表达和对进行性高血压的抗性。因此，我们假设肾 ATRAP 表达的下调与慢性肾脏病残余肾模型中高血压的发病机制有关。有趣的是，在高血压抗性 C57BL/6 背景下敲除 ATRAP 的小鼠进行 5/6 肾切除术后会导致高血压和血浆容量增加。此外，与野生型 C57BL/6 小鼠相比，在 5/6 肾切除术后，敲除与野生型相比，肾脏上皮钠通道 α 亚基和肿瘤坏死因子-α 的表达明显增强，同时肾脏中的血管紧张素 II 型 1 型受体的质膜表达增加。因此，肾 ATRAP 的下调参与了肾质量减少引起的血压升高的发生和进展，并且暗示 ATRAP 是慢性肾脏病中高血压的治疗靶标。
