Prostaglandin Ep4 Receptors In Kidney Epithelial Cells Promote Resistance To Hypertension.

A role for prostanoids in blood pressure control is demonstrated by clinical studies showing that use of nonsteroidal anti-inflammatory drugs, which block all the prostanoid production, is associated with hypertension. Prostaglandin E 2 (PGE 2 ) is a major prostanoid produced by the kidney and its actions are mediated by four E-prostanoid (EP) receptors: EP1-EP4. In previous studies, we found that conditional deletion of EP4R from all tissues in adult mice dramatically exaggerates Ang II-dependent hypertension, suggesting a powerful effect of EP4R to resist blood pressure elevation. We also found that elimination of EP4R from vascular smooth muscle cells did not affect severity of hypertension, indicating other cellular targets of PGE 2 must mediate this anti-hypertensive effect. Here we report studies examining actions of EP4R in two additional candidate cell lineages: macrophages and kidney epithelial cells, which have both been implicated in hypertension pathogeneses. Cell-specific deletion of EP4R was accomplished by crossing mice bearing a conditional EP4 allele ( EP4 flox ) with mouse lines carrying a LyzM-Cre + transgene expressing in macrophages (MACKOs) or tetracycline-inducible Pax8-rtTA + TetO-Cre + transgene driving expression in renal tubular epithelial cells (RTKOs). Elimination of EP4R from macrophages in MACKOs had minimal effects on baseline BP and salt sensitivity, and responses to chronic Ang II infusion were virtually identical in MACKOs and controls (138±3 vs 133±2 mm Hg; n=14/group). By contrast, absence of EP4R from kidney epithelia in RTKOs caused significant augmentation of Ang II-induced hypertension compared to Controls (average MAP: 145±4 vs. 135±3 mmHg, p=0.03; MAP increase from baseline: 31±2 vs. 20±3 mmHg, p=0.02). The increased severity of hypertension in RTKOs was associated with exaggerated cardiac hypertrophy relative to controls (heart:body weight ratio 8.6±1.5 vs. 7.3±1.2 mg/g; p=0.03). Our findings suggest that kidney epithelial cells, but not macrophages, are critical targets of PGE 2 acting via EP4R to oppose the development of hypertension. As collecting duct is the major site of EP4R expression in renal epithelia, this may reflect actions of EP4R to modulate key sodium transporters in this nephron segment.