Ramzi Hassouneh1, Rania Nasrallah1, Joe Zimpelmann2, Alex Gutsol2, David Eckert1, Jamie Ghossein1, Kevin D Burns1,2, Richard L Hébert3. 1. Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5. 2. Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. 3. Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5. rlhebert@uottawa.ca.
Abstract
AIMS/HYPOTHESIS: The first clinical manifestation of diabetes is polyuria. The prostaglandin E2 (PGE2) receptor EP3 antagonises arginine vasopressin (AVP)-mediated water reabsorption and its expression is increased in the diabetic kidney. The purpose of this work was to study the contribution of EP3 to diabetic polyuria and renal injury. METHODS: Male Ep 3 (-/-) (also known as Ptger3 (-/-)) mice were treated with streptozotocin (STZ) to generate a mouse model of diabetes and renal function was evaluated after 12 weeks. Isolated collecting ducts (CDs) were microperfused to study the contribution of EP3 to AVP-mediated fluid reabsorption. RESULTS: Ep 3 (-/-)-STZ mice exhibited attenuated polyuria and increased urine osmolality compared with wild-type STZ (WT-STZ) mice, suggesting enhanced water reabsorption. Compared with WT-STZ mice, Ep 3 (-/-)-STZ mice also had increased protein expression of aquaporin-1, aquaporin-2, and urea transporter A1, and reduced urinary AVP excretion, but increased medullary V2 receptors. In vitro microperfusion studies indicated that Ep 3 (-/-) and WT-STZ CDs responded to AVP stimulation similarly to those of wild-type mice, with a 60% increase in fluid reabsorption. In WT non-injected and WT-STZ mice, EP3 activation with sulprostone (PGE2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP3. A major finding of this work is that Ep 3 (-/-)-STZ mice showed blunted renal cyclooxygenase-2 protein expression, reduced renal hypertrophy, reduced hyperfiltration and reduced albuminuria, as well as diminished tubular dilation and nuclear cysts. CONCLUSIONS/ INTERPRETATION: Taken together, the data suggest that EP3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP3 may prove to be a promising target for more selective management of diabetic kidney disease.
AIMS/HYPOTHESIS: The first clinical manifestation of diabetes is polyuria. The prostaglandin E2 (PGE2) receptor EP3 antagonises arginine vasopressin (AVP)-mediated water reabsorption and its expression is increased in the diabetic kidney. The purpose of this work was to study the contribution of EP3 to diabetic polyuria and renal injury. METHODS: Male Ep 3 (-/-) (also known as Ptger3 (-/-)) mice were treated with streptozotocin (STZ) to generate a mouse model of diabetes and renal function was evaluated after 12 weeks. Isolated collecting ducts (CDs) were microperfused to study the contribution of EP3 to AVP-mediated fluid reabsorption. RESULTS:Ep 3 (-/-)-STZmice exhibited attenuated polyuria and increased urine osmolality compared with wild-type STZ (WT-STZ) mice, suggesting enhanced water reabsorption. Compared with WT-STZmice, Ep 3 (-/-)-STZmice also had increased protein expression of aquaporin-1, aquaporin-2, and urea transporter A1, and reduced urinary AVP excretion, but increased medullary V2 receptors. In vitro microperfusion studies indicated that Ep 3 (-/-) and WT-STZCDs responded to AVP stimulation similarly to those of wild-type mice, with a 60% increase in fluid reabsorption. In WT non-injected and WT-STZmice, EP3 activation with sulprostone (PGE2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP3. A major finding of this work is that Ep 3 (-/-)-STZmice showed blunted renal cyclooxygenase-2 protein expression, reduced renal hypertrophy, reduced hyperfiltration and reduced albuminuria, as well as diminished tubular dilation and nuclear cysts. CONCLUSIONS/ INTERPRETATION: Taken together, the data suggest that EP3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP3 may prove to be a promising target for more selective management of diabetic kidney disease.
Authors: Donald T Ward; S Kam Yau; Andrew P Mee; E Barbara Mawer; Christopher A Miller; Hugh O Garland; Daniela Riccardi Journal: J Am Soc Nephrol Date: 2001-04 Impact factor: 10.121
Authors: Joseph Ck Leung; Loretta Yy Chan; Anita Wl Tsang; Sydney Cw Tang; Kar Neng Lai Journal: Nephrology (Carlton) Date: 2005-02 Impact factor: 2.506
Authors: Franck A Belibi; Gail Reif; Darren P Wallace; Tamio Yamaguchi; Lincoln Olsen; Hong Li; George M Helmkamp; Jared J Grantham Journal: Kidney Int Date: 2004-09 Impact factor: 10.612
Authors: Xiaofang Wang; Yanhong Wu; Christopher J Ward; Peter C Harris; Vicente E Torres Journal: J Am Soc Nephrol Date: 2007-11-21 Impact factor: 10.121
Authors: David Z I Cherney; James W Scholey; Rania Nasrallah; Maria G Dekker; Cameron Slorach; Timothy J Bradley; Richard L Hébert; Etienne B Sochett; Judith A Miller Journal: Am J Physiol Renal Physiol Date: 2008-04-09
Authors: Jian Hua Li; Chung-Lin Chou; Bo Li; Oksana Gavrilova; Christoph Eisner; Jürgen Schnermann; Stasia A Anderson; Chu-Xia Deng; Mark A Knepper; Jürgen Wess Journal: J Clin Invest Date: 2009-10 Impact factor: 14.808
Authors: Rania Nasrallah; Joseph Zimpelmann; David Eckert; Jamie Ghossein; Sean Geddes; Jean-Claude Beique; Jean-Francois Thibodeau; Chris R J Kennedy; Kevin D Burns; Richard L Hébert Journal: Lab Invest Date: 2017-12-18 Impact factor: 5.662
Authors: Alex A Gutsol; Paula Blanco; Taben M Hale; Jean-Francois Thibodeau; Chet E Holterman; Rania Nasrallah; Jose W N Correa; Sergey A Afanasiev; Rhian M Touyz; Chris R J Kennedy; Dylan Burger; Richard L Hébert; Kevin D Burns Journal: PLoS One Date: 2022-02-17 Impact factor: 3.240
Authors: Jaclyn A Wisinski; Austin Reuter; Darby C Peter; Michael D Schaid; Rachel J Fenske; Michelle E Kimple Journal: Am J Physiol Endocrinol Metab Date: 2021-07-06 Impact factor: 4.310