TRPC6 Enhances Angiotensin II-induced Albuminuria
TRPC6 Enhances Angiotensin II-induced Albuminuria
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DOI：
10.1681/asn.2010050522
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发表时间：
2011-03-01
影响因子：
13.6
通讯作者：
Winn, Michelle P.
中科院分区：
文献类型：
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作者：
Eckel, Jason;Lavin, Peter J.;Winn, Michelle P.
经典瞬时受体电位阳离子通道6（TRPC6）的突变是导致成人发病的局灶节段性肾小球硬化症（FSGS）家族性形式的原因。TRPC6突变导致肾脏疾病的机制尚未完全清楚。我们使用TRPC6缺陷小鼠来研究TRPC6在肾脏中的功能。我们发现成年TRPC6缺陷小鼠的血压和白蛋白排泄率与野生型动物相似。肾小球组织形态学在光镜和电镜下均未显示异常。为了确定缺乏TRPC6是否会改变对高血压和肾损伤的易感性，我们给小鼠连续输注血管紧张素II 28天。尽管两组都出现了相似程度的高血压，但TRPC6缺陷小鼠的蛋白尿明显更少，尤其是在输注的早期阶段；这表明TRPC6对肾小球滤过有不利影响。我们使用全细胞膜片钳记录来测量野生型和TRPC6缺陷小鼠足细胞原代培养物中的细胞膜电流。在野生型小鼠的足细胞中，血管紧张素II和TRPC6的直接激活剂都增加了细胞膜电流；TRPC6缺陷消除了这些电流幅度的增加。我们的研究结果表明，TRPC6可能通过促进血管紧张素II依赖性的Ca2+增加来促进蛋白尿，这表明阻断TRPC6可能对蛋白尿性肾脏疾病有治疗益处。
Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca2+, suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.