Glomerular VEGF resistance induced by PKCβ/SHP-1 activation and contribution to diabetic nephropathy

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