Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats
Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats
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DOI：
10.1172/jci119503
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发表时间：
1997-07-01
影响因子：
15.9
通讯作者：
King, GL
中科院分区：
文献类型：
--
作者：
Koya, D;Jirousek, MR;King, GL
高血糖诱导血管组织中的蛋白激酶C(PKC)通路与糖尿病并发症中观察到的许多细胞变化有关。最近，我们报道了一种新的，口服有效的PKCβ亚型特异性抑制剂(LY333531)的使用使许多早期糖尿病大鼠的视网膜和肾脏血流动力学正常化。在本研究中，我们描述了与葡萄糖或糖尿病引起的培养的肾小球系膜细胞和肾小球的慢性变化相关的一系列生化和分子异常，而LY333531可以预防这种异常；高血糖使暴露于高浓度葡萄糖的培养的肾小球系膜细胞二酰甘油(DAG)水平增加，并激活糖尿病大鼠肾小球的PKCα和β1亚型。在糖尿病大鼠系膜细胞中加入PKCβ选择性抑制剂(LY333531)可在不降低DAG水平的情况下抑制高糖激活的PKC活性，而口服LY333531可特异性地抑制PKCβ1亚型的激活而不降低PKCα亚型的激活。加入LY333531可完全阻止葡萄糖诱导的系膜细胞花生四烯酸释放、前列腺素E-2的产生以及对Na+-K+ATPase活性的抑制。口服LY333531可抑制糖尿病大鼠肾小球转化生长因子-β1和细胞外基质成分如纤维连接蛋白和α1(IV)的mRNA表达，同时抑制PKC活性和α1(IV)胶原。这些结果提示，高血糖引起的肾小球系膜细胞和肾小球PKC，主要是β亚型的激活，可能通过改变前列腺素合成和Na~+-K~+-ATPase活性而导致早期肾功能不全，也可能通过转化生长因子-β1和细胞外基质成分基因的过度表达而导致慢性病理改变。
Induction of protein kinase C (PKC) pathway in the vascular tissues by hyperglycemia has been associated with many of the cellular changes observed in the complications of diabetes. Recently, we have reported that the use of a novel, orally effective specific inhibitor of PKC beta isoform (LY333531) normalized many of the early retinal and renal hemodynamics in rat models of diabetes, In the present study, we have characterized a spectrum of biochemical and molecular abnormalities associated with chronic changes induced by glucose or diabetes in the cultured mesangial cells and renal glomeruli that can be prevented by LY333531, Hyperglycemia increased diacylglycerol (DAG) level in cultured mesangial cells exposed to high concentrations of glucose and activated PKC alpha and beta 1 isoforms in the renal glomeruli of diabetic rats. The addition of PKC beta selective inhibitor (LY333531) to cultured mesangial cells inhibited activated PKC activities by high glucose without lowering DAG levels and LY333531 given orally in diabetic rats specifically inhibited the activation of PKC beta 1 isoform without decreasing PKC alpha isoform activation, Glucose-induced increases in arachidonic acid release, prostaglandin E-2 production, and inhibition of Na+-K+ ATPase activities in the cultured mesangial cells were completely prevented by the addition of LY333531, Oral feeding of LY333531 prevented the increased mRNA expression of TGF-beta 1 and extracellular matrix components such as fibronectin and alpha 1(IV) collagen in the glomeruli of diabetic rats in parallel with inhibition of glomerular PKC activity, These results suggest that the activation of PKC, predominately the beta isoform by hyperglycemia in the mesangial cells and glomeruli can partly contribute to early renal dysfunctions by alteration of prostaglandin production and Na+-K+ ATPase activity as well as the chronic pathological changes by the overexpression of TGF-beta 1 and extracellular matrix components genes.