A Maladaptive Role for EP4 Receptors in Podocytes

作者：Stitt Cavanagh Erin M; Faour Wissam H; Takami Kaede; Carter Anthony; Vanderhyden Barbara; Guan Youfei; Schneider Andre; Breyer Matthew D; Kennedy Christopher R J^*

来源：Journal of the American Society of Nephrology, 2010, 21(10): 1678-1690.

DOI：10.1681/ASN.2009121234

Inhibition of p38 mitogen-activated protein kinase and cyclooxygenase-2 reduces albuminuria in models of chronic kidney disease marked by podocyte injury. Previously, we identified a feedback loop in podocytes whereby an in vitro surrogate for glomerular capillary pressure (i.e., mechanical stretch) along with prostaglandin E, stimulation of its EP4 receptor induced cyclooxygenase-2 in a p38-dependent manner. Here we asked whether stimulation of EP4 receptors would exacerbate glomerulopathies associated with enhanced glomerular capillary pressure. We generated mice with either podocyte-specific overexpression or depletion of the EP4 receptor (EP4(Pod+) and EP4(Pod-/-), respectively). Glomerular prostaglandin E(2)-stimulated cAMP levels were eightfold greater for EP4(Pod+) mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were > 50% lower, and prostaglandin E(2)-induced CAMP synthesis was absent in podocytes isolated from EP4(Pod-/-) mice. Non-TG and EP4(Pod+) mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (+25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4(Pod+) mice (3438 mu g/mg) was significantly higher than that of non-TG mice (773 mu g/mg; P < 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4(Pod+) mice was significantly lower than that for non-TG mice (14 versus 67%). In contrast, 6 weeks after nephrectomy, the albumin-creatinine ratio of EP4(Pod-/-) mice (753 mu g/mg) was significantly lower than that of non-TG mice (2516 mu g/mg; P < 0.05). These findings suggest that prostaglandin E(2), acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.

• 出版日期2010-10
• 单位北京大学