CD)-derived endothelin-1 (ET-1) is an important regulator of systemic blood pressure and renal Na and water excretion. Based on this work, we hypothesize the following: CD ET-1 production is increased in IcondRitieocnesnt nsetucedsiesitatinfrgom eonuhranlacebdoratoNrya, anudtiliwziantger cexllc-srepteiocnific angdenredutcaergdetinbglo, odinpdriceastseure.thatActiovlaleticotning ofdCucDt ETB receptors and medullary interstitial cell ET receptors increases medullary nitric oxide and PGE2 production, while activation of CD ETA receptors enhances superoxide formation which reduces nitric oxide. Nitric oxide and PGE2 inhibit CD Na and/or water reabsorption and dilate medullary vasa recta. The resultant Na and water excretion limits hypertension in the setting of Na loading or mineralocorticoid excess. CD ET-1 may play a different role in angiotensin II hypertension due to angiotensin II down-regulation of the medullary ET-1 system. This system is also crucial in mediating vasopressin escape. Overall, the CD ET-1 system is essential in controlling blood pressure under normal physiologic as well as pathologic conditions. Mice with CD-specific knockout of ET-1, ETA receptor, ETB receptor, or both ETA and ETB receptors will be used. The mechanisms of ET-1 regulation of renal function and blood pressure under normal physiologic circumstances will be studied. This includes determination of whether CD-derived ET-1 acts in an autocrine and/or paracrine fashion, whether ETA and ETB receptors have opposing effects on Na and water excretion and blood pressure, whether and how CD-derived ET-1 regulates medullary blood flow, significance and mechanisms of CD-derived ET-1 interaction with nitric oxide, PGE2 and superoxide systems, and whether CD-derived ET-1 causes long-term changes in CD Na and water transporter expression. In addition, CD- derived ET-1 regulation of blood pressure and renal function under salt and/or water retaining conditions will be examined. This will include determination of the role of CD-derived ET-1 in controlling blood pressure and/or maintaining renal function in DOCA/salt hypertension, angiotensin II hypertension, and AVP excess. These studies will provide information on the role of CD-derived ET-1 in controlled blood pressure and renal function under normal physiologic as well as pathologic conditions. Such information is important in understanding intrarenal mechanisms responsible for hypertension and salt and water retention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK069392-03S1
Application #
7417672
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ketchum, Christian J
Project Start
2005-02-01
Project End
2009-11-30
Budget Start
2007-07-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$17,441
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kohan, Donald E (2014) Moving from trainee to junior: faculty: a brief guide. Physiologist 57:3-6
Jhaveri, Kenar D; Sparks, Matthew A; Shah, Hitesh H et al. (2013) Why not nephrology? A survey of US internal medicine subspecialty fellows. Am J Kidney Dis 61:540-6
Shapiro, Shelley; Pollock, David M; Gillies, Hunter et al. (2012) Frequency of edema in patients with pulmonary arterial hypertension receiving ambrisentan. Am J Cardiol 110:1373-7
Kohan, Donald E; Cleland, John G; Rubin, Lewis J et al. (2012) Clinical trials with endothelin receptor antagonists: what went wrong and where can we improve? Life Sci 91:528-39
Andress, Dennis L; Coll, Blai; Pritchett, Yili et al. (2012) Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD). Life Sci 91:739-42
Stricklett, Peter K; Strait, Kevin A; Kohan, Donald E (2011) Novel regulation of endothelin-1 promoter activity by protein kinase C. Cell Biochem Biophys 61:643-50
Kohan, Donald E; Rossi, Noreen F; Inscho, Edward W et al. (2011) Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 91:1-77
Rabelink, Ton J; Kohan, Donald E (2011) Endothelin receptor blockade in patients with diabetic nephropathy. Contrib Nephrol 172:235-42
Kohan, Donald E (2010) Endothelin, hypertension and chronic kidney disease: new insights. Curr Opin Nephrol Hypertens 19:134-9
Raphael, Kalani L; Strait, Kevin A; Stricklett, Peter K et al. (2009) Inactivation of Pkd1 in principal cells causes a more severe cystic kidney disease than in intercalated cells. Kidney Int 75:626-33

Showing the most recent 10 out of 12 publications