Submitted on October 20, 2008
Revised on April 23, 2009
Accepted on April 24, 2009
SOD1-Deficiency Causes Salt-Sensitivity and Aggravates Hypertension in Hydronephrosis
Mattias Carlstrom1*, Russell D Brown2, Johan Sallstrom, Erik Larsson1, Mihkel Zilmer3, Sheller Zabihi1, Ulf J. Eriksson4, and A. Erik G. Persson1
1 Uppsala University
2 Monash University
3 Tartu University
4 University of Uppsala
* To whom correspondence should be addressed. E-mail: mattias.carlstrom{at}mcb.uu.se.
Background: Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with NO-deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt-sensitivity and for hypertension in hydronephrosis. Methods: Hydronephrosis was induced in SOD1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko) and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high sodium (4% NaCl) diets and with chronic Tempol supplementation. 8-iso-prostaglandin-F2
(F2-IsoPs) and protein excretion profiles and histology were investigated. The acute effects of Tempol on blood pressure and TGF were studied in rats. Results: In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114±1 to 120±2 mmHg) which was augmented in SOD1-ko (125±3 to 135±4 mmHg), but abolished in SOD1-tg (109±3 to 108±3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108±1 to 115±2 mmHg), which was not found in wild-types or SOD1-tg. Chronic Tempol treatment reduced blood pressure in SOD1-ko controls (-7 mmHg) and in hydronephrotic wild-types (-8 mmHg) and SOD1-ko mice (-16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-types were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis (
PSF: 15.2±1.2 to 9.1±0.6 mmHg, TP: 14.3±0.8 to 19.7±1.4 nl/min). Conclusion: Oxidative stress due to SOD1-deficiency causes salt-sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension.
