Prostaglandin E2 receptor EP1 (PGE2/EP1) promotes diabetic renal injury, and EP1 receptor deletion improves hyperfiltration, albuminuria, and fibrosis. The role of EP1 receptors in hypertensive kidney disease (HKD) remains controversial. We examined the contribution of EP1 receptors to HKD. EP1 null (EP1−/−) mice were bred with hypertensive TTRhRen mice (Htn) to evaluate kidney function and injury at 24 weeks. EP1 deletion had no effect on elevation of systolic blood pressure in Htn mice (HtnEP1−/−) but resulted in pronounced albuminuria and reduced FITC-inulin clearance, compared with Htn or wild-type (WT) mice. Ultrastructural injury to podocytes and glomerular endothelium was prominent in HtnEP1−/− mice; including widened subendothelial space, subendothelial lucent zones and focal lifting of endothelium from basement membrane, with focal subendothelial cell debris. Cortex COX2 mRNA was increased by EP1 deletion. Glomerular EP3 mRNA was reduced by EP1 deletion, and EP4 by Htn and EP1 deletion. In WT mice, PGE2 increased chloride reabsorption via EP1 in isolated perfused thick ascending limb (TAL), but PGE2 or EP1 deletion did not affect vasopressin-mediated chloride reabsorption. In WT and Htn mouse inner medullary collecting duct (IMCD), PGE2 inhibited vasopressin-water transport, but not in EP1−/− or HtnEP1−/− mice. Overall, EP1 mediated TAL and IMCD transport in response to PGE2 is unaltered in Htn, and EP1 is protective in HKD.
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Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2224–60.
Olsen MH, Angell SY, Asma S, Boutouyrie P, Burger D, Chirinos JA, et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: The Lancet Commission on hypertension. Lancet. 2016;388:2665–712.
Harcourt BE, Penfold SA, Forbes JM. Coming full circle in diabetes mellitus: from complications to initiation. Nat Rev Endocrinol. 2013;9:113–23.
Nasrallah R, Hassouneh R, Hébert RL. Chronic kidney disease: Targeting prostaglandin E2 receptors. Am J Physiol Renal Physiol. 2014;307:F243–50.
Swan CE, Breyer RM. Prostaglandin E2 modulation of blood pressure homeostasis: studies in rodent models. Prostaglandins Other Lipid Mediat. 2011;96:10–3.
Gurwitz JH, Avorn J, Bohn RL, Glynn RJ, Monane M, Mogun H. Initiation of antihypertensive treatment during nonsteroidal anti-inflammatory drug therapy. JAMA. 1994;272:781–6.
Yang T. Microsomal prostaglandin E synthase-1 and blood pressure regulation. Kidney Int. 2007;72:274–8.
Whelton A, White WB, Bello AE, Puma JA, Fort JG. Effects of celecoxib and rofecoxib on blood pressure and edema in patients or 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol. 2002;90:959–63.
White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension. 2002;39:929–34.
Nasrallah R, Hassouneh R, Hébert RL. Prostaglandin E2, kidney disease, and cardiovascular risk: beyond hypertension and diabetes. J Am Soc Nephrol. 2016;27:666–76.
Nasrallah R, Robertson SJ, Karsh J, Hébert RL. Celecoxib modifies glomerular basement membrane, mesangial area and podocyte structure in OVE26 mice, but ibuprofen is more detrimental. Clin Sci. 2013;124:685–94.
Nasrallah R, Robertson SJ, Hébert RL. Chronic COX inhibition reduces diabetes-induced hyperfiltration, proteinuria, and renal pathological markers in 36-week B6-Ins2(Akita) mice. Am J Nephrol. 2009;30:346–53.
Nasrallah R, Xiong H, Hébert RL. Renal prostaglandin E2 receptor (EP) expression profile is altered in streptozotocin and B6-Ins2Akita type 1 diabetic mice. Am J Physiol. 2007;292:278–84.
Cherney DZ, Miller JA, Scholey JW, Nasrallah R, Hébert RL, Dekker MG, et al. Renal hyperfiltration is a determinant of endothelial function responses to cyclooxygenase 2 inhibition in type 1 diabetes. Diabetes Care. 2010;33:1344–6.
Cherney DZI, Miller J, Scholey JW, Bradley TJ, Slorach C, Curtis JR, et al. The effect of cyclooxygenase 2 inhibition on renal hemodynamic function in humans with type 1 diabetes mellitus. Diabetes. 2008;57:688–95.
Cherney DZ, Scholey JW, Nasrallah R, Dekker MG, Slorach C, Bradley TJ, et al. Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2008;294:F1336–41.
Thibodeau JF, Nasrallah R, Hébert RL, Kennedy C. Reduced albuminuria in diabetic PTGER1-null mice. Am J Pathol. 2013;183:1789–802.
Makino H, Tanaka I, Mukoyama M, Sugawara A, Mori K, Muro S, et al. Prevention of diabetic nephropathy in rats by prostaglandin E receptor EP1-selective antagonist. J Am Soc Nephrol. 2002;13:1757–65.
Rutkai I, Feher A, Erdei N, Henrion D, Papp Z, Edes I, et al. Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes. Cardiovasc Res. 2009;83:148–54.
Suganami T, Mori K, Tanaka I, Mukoyama M, Sugawara A, Makino H, et al. Role of prostaglandin E receptor EP1 subtype in the development of renal injury in genetically hypertensive rats. Hypertension. 2003;42:1183–90.
Bartlett CS, Boyd KL, Harris RC, Zent R, Breyer RM. EP1 disruption attenuates end-organ damage in a mouse model of hypertension. Hypertension. 2012;60:1184–91.
Nasrallah R, Zimpelmann J, Eckert D, Ghossein J, Geddes S, Beique JC, et al. PGE2/EP1 receptor inhibits vasopressin-dependent water reabsorption and sodium transport in mouse collecting duct. Lab Invest. 2018;98:360–70.
Kennedy CRJ, Xiong H, Rahal S, Vanderluit J, Slack R, Zhang Y, et al. Urine concentrating defect in prostaglandin EP1-Deficient mice. Am J Physiol. 2007;292:F868–75.
Araki K, Imaizumi T, Sekimoto T, Yoshinobu K, Yoshimuta J, Akizuki M, et al. Exchangeable gene trap using the Cre/mutated lox system. Cell Mol Biol. 1999;45:737–50.
Thibodeau JF, Holterman CE, Burger D, Read NC, Reudelhuber TL, Kennedy CR. A novel mouse model of advanced diabetic kidney disease. PLoS One. 2014;9:e113459.
Hassouneh R, Nasrallah R, Zimpelmann J, Gutsol A, Eckert D, Ghossein J, et al. PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes. Diabetologia. 2016;59:1318–28.
Wehbi GJ, Zimpelmann J, Carey RM, Levine DZ, Burns KD. Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. Am J Physiol Renal Physiol. 2001;280:F254–65.
Burger D, Thibodeau JF, Holterman CE, Burns KD, Touyz RM, Kennedy CR. Urinary podocyte microparticles identify prealbuminuric diabetic glomerular injury. J Am Soc Nephrol. 2014;25:1401–7.
Raij L, Azar S, Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984;26:137–43.
Weibel ER. Sterological Method: Practical Methods of Biological Morphometry. Vol. 1. London: Academic Press; 1979.
Himmerkus N, Plain A, Marques RD, Sonntag SR, Paliege A, Leipziger J, et al. AVP dynamically increases paracellular Na+ permeability and transcellular NaCl transport in the medullary thick ascending limb of Henle’s loop. Pflugers Arch - Eur J Physiol. 2017;469:149–58.
Stock JL, Shinjo K, Burkhardt J, Roach M, Taniguchi K, Ishikawa T, et al. The prostaglandin E2/EP1 receptor mediates pain perception and regulates blood pressure. J Clin Invest. 2001;107:325–31.
Guan Y, Zhang Y, Wu J, Qi Z, Yang G, Dou D, et al. Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. J Clin Invest. 2007;117:2496–505.
Peterson LN, McKay AJ, Borzecki JS. Endogenous Prostaglandin E2 Mediates Inhibition of Rat Thick Ascending Limb CI Reabsorption in Chronic Hypercalcemia. J Clin Invest. 1993;91:2399–407.
Culpepper RM, Andreoli TE. Interactions among Prostaglandin E2, Antidiuretic Hormone, and Cyclic Adenosine Monophosphate in Modulating Cl- Absorption in Single Mouse Medullary Thick Ascending Limbs of Henle. J Clin Invest. 1983;71:1588–601.
Kaji DM, Chase HS Jr, Eng JP, Diaz J. Prostaglandin E2 inhibits Na-K-2Cl cotransport in medullary thick ascending limb cells. Am J Physiol Cell Physiol. 1996;271:C354–61.
Rajagopal M, Thomas SV, Kathpalia PP, Chen Y, Pao AC. Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells. Am J Physiol Cell Physiol. 2014;306:C263–78.
Sandrasagra S, Cuffe JE, Regardsoe EL, Korbmacher C. PGE2 stimulates Cl- secretion in murine M-1 cortical collecting duct cells in an autocrine manner. Pflügers Arch. 2004;448:411–21.
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Nasrallah, R., Zimpelmann, J., Robertson, S.J. et al. Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice. Lab Invest 100, 414–425 (2020). https://doi.org/10.1038/s41374-019-0317-7