Glomerular VEGF resistance induced by PKCβ/SHP-1 activation and contribution to diabetic nephropathy
Glomerular VEGF resistance induced by PKCβ/SHP-1 activation and contribution to diabetic nephropathy
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DOI：
10.1096/fj.11-202994
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
King, George L.
中科院分区：
文献类型：
--
作者：
Mima, Akira;Kitada, Munehiro;King, George L.
本研究描述了葡萄糖诱导的蛋白激酶C δ（PKC δ）和含Src同源性2结构域的磷酸酶-1（SHP-1）表达活化对培养的肾小球足细胞和糖尿病啮齿动物肾小球中血管内皮生长因子（VEGF）作用的影响。葡萄糖水平升高诱导PKC δ和p38丝裂原活化蛋白激酶（p38 MAPK）增加SHP-1表达，增加足细胞凋亡，并抑制足细胞和肾小球内皮细胞中VEGF的活化。高葡萄糖水平的不利影响可以被PKC δ、p38 MAPK和SHP-1的分子抑制剂抵消，并且仅部分地被抗氧化剂和核因子-κ B（NF-κ B）抑制剂降低。糖尿病大鼠和小鼠肾小球中PKC δ活化和SHP-1表达的增加与VEGF信号转导和足细胞数量的丧失相关。相反，糖尿病PKC δ-敲除（Prkcd（-/-））小鼠在肾小球中没有表现出p38 MAPK和SHP-1的激活或VEGF信号传导的抑制.在功能上，糖尿病Prkcd（-/-）小鼠的TGF β、VEGF和细胞外基质表达减少，白蛋白尿少于糖尿病Prkcd（+/+）小鼠。高血压和糖尿病可引起肾小球足细胞凋亡和内皮功能障碍，部分原因是PKC β/p38 MAPK活化增加和SHP-1表达增加，导致VEGF抵抗，而不依赖于NF-κ B活化。米马，A.，Kitada，M.，Geraldes，P.，李，Q.，松本，M.，Mizutani，K.，齐，W.，Li，C.，Leitges，M.，Rask-Madsen，C.，金角，澳-地L. PKC δ/SHP-1激活诱导的肾小球VEGF抵抗与糖尿病肾病的关系FASEB J.26，2963-2974（2012）。www.fasebj.org
This study characterizes the effect of glucose-induced activation of protein kinase C delta (PKC delta) and Src homology-2 domain-containing phosphatase-1 (SHP-1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKC delta and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKC delta, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-kappa B (NF-kappa B) inhibitor. Increased PKC delta activation and SHP-1 expression correlated with loss of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and mice. In contrast, diabetic PKC delta -knockout (Prkcd(-/-)) mice did not exhibit activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of TGF beta, VEGF, and extracellular matrix and less albuminuria than diabetic Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte apoptosis and endothelial dysfunction partly due to increased PKC beta/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-kappa B activation.-Mima, A., Kitada, M., Geraldes, P., Li, Q., Matsumoto, M., Mizutani, K., Qi, W., Li, C., Leitges, M., Rask-Madsen, C., King, G. L. Glomerular VEGF resistance induced by PKC delta/SHP-1 activation and contribution to diabetic nephropathy. FASEB J. 26, 2963-2974 (2012). www.fasebj.org