A maladaptive role for EP4 receptors in podocytes.
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(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 μg/mg) was significantly higher than that of non-TG mice (773 μg/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 μg/mg) was significantly lower than that of non-TG mice (2516 μg/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.
Stitt-Cavanagh
Erin M
EM
Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Faour
Wissam H
WH
Takami
Kaede
K
Carter
Anthony
A
Vanderhyden
Barbara
B
Guan
Youfei
Y
Schneider
Andre
A
Breyer
Matthew D
MD
Kennedy
Christopher R J
CR
D000419:Albuminuria / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D007668:Kidney / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype
C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2