SOD1-Deficiency Causes Salt-Sensitivity and Aggravates Hypertension in Hydronephrosis

• 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-F2alpha (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 (DeltaPSF: 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.

Nyckelord

blood pressure

CuZnSOD

isoprostanes

superoxide

telemetry

tempol

tubuloglomerular feedback

ureteral obstruction

oxidative stress

MEDICINE

MEDICIN

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