Expression of heme oxygenase-1 in thick ascending loop of henle attenuates angiotensin II-dependent hypertension.
Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (139 ± 3 versus 153 ±2 mmHg in the transgenic and control mice, respectively; P<0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption.
Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, 39216, USA. dstec@umc.edu
David E
DE
Stec
Heather A
HA
Drummond
Monette U
MU
Gousette
Megan V
MV
Storm
Nader G
NG
Abraham
Eva
E
Csongradi
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005665:Furosemide / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006973:Hypertension / Q000209:etiology / Q000517:prevention & control*; D008138:Loop of Henle / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D010042:Ouabain / Q000494:pharmacology; D012413:Rubidium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000032:analysis; D028021:Sodium-Potassium-Chloride Symporters / Q000032:analysis; D064466:Solute Carrier Family 12, Member 1; D058949:Uromodulin / Q000032:analysis / Q000502:physiology
C578714:SLC12A1 protein, human; C578715:Slc12a1 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D058949:Uromodulin; D000804:Angiotensin II; D010042:Ouabain; D005665:Furosemide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D012413:Rubidium