Approaching epidemic levels, diabetic kidney disease (DKD) is now the leading cause of end-stage renal disease (ESRD). Microalbuminuria is an early clinical marker of DKD that results from damage to the glomerular filtration barrier at the level of the highly differentiated glomerular podocyte cells. Injury to these epithelial cells, podocytopathies, includes cellular hypertrophy, foot process effacement, detachment from the glomerular basement membrane, and apoptosis. Here we review the role of a number of recently identified factors that contribute to podocytopathies in DKD. These factors include members of the renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) types 1 and 2, prorenin and its receptor, reactive oxygen species (ROS), prostanoids, peroxisome proliferator-activated receptors (PPAR), advanced glycation end-products (AGEs) and their receptors (RAGE), adiponectin, and microRNAs. As the number of therapeutic options that slow, but do not halt, the progression of DKD to ESRD remains limited, a more comprehensive understanding of the signaling events that contribute to this increasingly prevalent disease may identify novel avenues for treatment and prevention.

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 2 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 podϩ and EP4 podϪ/Ϫ , respectively). Glomerular prostaglandin E 2 -stimulated cAMP levels were eightfold greater for EP4 podϩ mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were Ͼ50% lower, and prostaglandin E 2 -induced cAMP synthesis was absent in podocytes isolated from EP4 podϪ/Ϫ mice. Non-TG and EP4 podϩ mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (ϩ25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϩ mice (3438 g/mg) was significantly higher than that of non-TG mice (773 g/mg; P Ͻ 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4 podϩ 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 podϪ/Ϫ mice (753 g/mg) was significantly lower than that of non-TG mice (2516 g/mg; P Ͻ 0.05). These findings suggest that prostaglandin E 2 , acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.