Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-β1-connective tissue growth factor signalling cascade.
Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-β1-connective tissue growth factor signalling cascade.
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DOI：
10.1111/j.1440-1681.2011.05486.x
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发表时间：
2011-04
影响因子：
2.9
通讯作者：
Siragy HM
中科院分区：
文献类型：
--
作者：
Huang J;Matavelli LC;Siragy HM
转化生长因子β1 （tgf - β1）和结缔组织生长因子（CTGF）在肾小球中表达，参与糖尿病肾病的发展。最近，我们证实（pro）肾素受体（PRR）在链脲佐菌素（STZ）诱导的糖尿病大鼠模型肾脏中上调。我们假设在高血糖的情况下，肾脏PRR表达的增加有助于tgf - β1- ctgf信号活性的增强，从而导致糖尿病肾病的发生。在Sprague-Dawley大鼠和大鼠系膜细胞（RMCs）中进行了体内和体外研究。在体内用prorenin的柄区肽（HRP）治疗STZ诱导的糖尿病大鼠，在体外用HRP或PRR siRNA在rmc中阻断PRR。缬沙坦治疗可阻断血管紧张素AT1受体。结果显示，PRR、TGFβ1和CTGF在糖尿病肾脏和高糖RMCs中表达上调。葡萄糖暴露也诱导PRR磷酸化，这一过程被HRP、缬沙坦或PRR siRNA抑制。HRP和缬沙坦可显著降低糖尿病动物和高糖RMCs中肾脏tgf - β1和CTGF的表达。在高葡萄糖暴露的RMCs中观察到类似的结果，以响应PRR siRNA。TGFβ受体阻断降低RMCs中CTGF的表达。缬沙坦联合PRR siRNA可进一步降低RMCs中tgf - β1和CTGF的表达。总之，PRR通过增强tgf - β1- ctgf信号级联参与糖尿病肾脏疾病。
Transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) are expressed in renal glomeruli and contribute to development of diabetic nephropathy. Recently we demonstrated that (pro)renin receptor (PRR) is upregulated in the kidneys of streptozocin (STZ)-induced diabetes rat model. We hypothesized that in the presence of hyperglycemia, increased renal PRR expression contributes to enhanced TGFβ1-CTGF signaling activity, leading to development of diabetic kidney disease. In vivo and in vitro studies were conducted in Sprague-Dawley rats and rat mesangial cells (RMCs). PRR blockade was achieved in vivo by treating STZ induced diabetes rats with the handle region peptide (HRP) of prorenin and in vitro by HRP or PRR siRNA in RMCs. Angiotensin AT1 receptor blockade was achieved by Valsartan treatment. Results showed that expression of PRR, TGFβ1 and CTGF were upregulated in diabetic kidneys and RMCs exposed to high glucose. Glucose exposure also induced PRR phosphorylation, a process that was inhibited by HRP, Valsartan or PRR siRNA. HRP and Valsartan significantly attenuated renal TGFβ1 and CTGF expression in diabetic animals and high glucose treated RMCs. Similar results were observed in high glucose exposed RMCs in response to PRR siRNA. TGFβ receptor blockade decreased CTGF expression in RMCs. Combined administration of Valsartan and PRR siRNA demonstrated further reduction of TGFβ1 and CTGF expression in RMCs. In conclusion, PRR contributes to kidney disease in diabetes through enhanced TGFβ1-CTGF signaling cascade.
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影响因子：
8.3
作者：
Muller, Dominik N.;Klanke, Bernd;Hilgers, Karl F.
通讯作者：
Hilgers, Karl F.
影响因子：
8.3
作者：
Border, WA;Noble, NA
通讯作者：
Noble, NA
影响因子：
15.9
作者：
KAGAMI, S;BORDER, WA;NOBLE, NA
通讯作者：
NOBLE, NA
DOI：
10.1152/ajprenal.00139.2003
发表时间：
2004-02-01
影响因子：
4.2
作者：
Naito, T;Masaki, T;Kohno, N
通讯作者：
Kohno, N
影响因子：
19.6
作者：
Nguyen, G;Delarue, F;Sraer, JD
通讯作者：
Sraer, JD