Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.
Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.
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DOI：
10.1016/j.kint.2018.09.026
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发表时间：
2019-02
影响因子：
19.6
通讯作者：
Liming Wang;Jae‐Hyung Chang;A. Buckley;R. Spurney
中科院分区：
文献类型：
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作者：
Liming Wang;Jae‐Hyung Chang;A. Buckley;R. Spurney
TRPC6 的功能获得性突变会导致家族性局灶节段性肾小球硬化症，并且 TRPC6 在包括糖尿病肾病在内的肾小球疾病中表达上调。我们研究了系统性 TRPC6 敲除对 1 型糖尿病秋田犬模型的影响。敲除 TRPC6 可抑制 12 周和 16 周龄秋田小鼠的蛋白尿，但这种差异在 20 周时消失。 TRPC6 的敲除也减少了秋田小鼠的肾小管损伤；然而，系膜扩张显着增加。 TRPC6 敲除小鼠和野生型秋田小鼠的高血糖和血压相似，但敲除小鼠的胰岛素抵抗程度更高。在培养的足细胞中，TRPC6 的敲除抑制了钙/钙调神经磷酸酶反应基因胰岛素受体底物 2 的表达，并降低了胰岛素反应性。据报道，胰岛素抵抗会促进糖尿病肾病，与血糖水平无关。虽然其机制尚不完全清楚，但胰岛素会激活 Akt2 和 ERK，从而抑制细胞凋亡信号调节激酶 1 (ASK1)-p38 诱导的细胞凋亡。在培养的足细胞中，高血糖刺激 p38 信号传导并诱导细胞凋亡，抑制胰岛素和 ASK1 可减少细胞凋亡，抑制 Akt 或 ERK 可增强细胞凋亡。 TRPC6 敲除秋田小鼠中肾小球 p38 信号传导增强，并与 p38 基因靶环加氧酶 2 的表达增强相关。这些数据表明，秋田小鼠中 TRPC6 敲除会促进胰岛素抵抗并加剧肾小球疾病，而与高血糖无关。
Gain-of-function mutations in TRPC6 cause familial focal segmental glomerulosclerosis, and TRPC6 is upregulated in glomerular diseases including diabetic kidney disease. We studied the effect of systemic TRPC6 knockout in the Akita model of type 1 diabetes. Knockout of TRPC6 inhibited albuminuria in Akita mice at 12 and 16 weeks of age, but this difference disappeared by 20 weeks. Knockout of TRPC6 also reduced tubular injury in Akita mice; however, mesangial expansion was significantly increased. Hyperglycemia and blood pressure were similar between TRPC6 knockout and wild-type Akita mice, but knockout mice were more insulin resistant. In cultured podocytes, knockout of TRPC6 inhibited expression of the calcium/calcineurin responsive gene insulin receptor substrate 2 and decreased insulin responsiveness. Insulin resistance is reported to promote diabetic kidney disease independent of blood glucose levels. While the mechanisms are not fully understood, insulin activates both Akt2 and ERK, which inhibits apoptosis signal regulated kinase 1 (ASK1)-p38–induced apoptosis. In cultured podocytes, hyperglycemia stimulated p38 signaling and induced apoptosis, which was reduced by insulin and ASK1 inhibition and enhanced by Akt or ERK inhibition. Glomerular p38 signaling was increased in TRPC6 knockout Akita mice and was associated with enhanced expression of the p38 gene target cyclooxygenase 2. These data suggest that knockout of TRPC6 in Akita mice promotes insulin resistance and exacerbates glomerular disease independent of hyperglycemia.