SOD1 deficiency causes salt sensitivity and aggravates hypertension in hydronephrosis

Abstract

Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt sensitivity and for hypertension in hydronephrosis. Hydronephrosis was induced in superoxide dismutase 1-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. The 8-iso-prostaglandin-F(2alpha) (F2-IsoPs) and protein excretion profiles and renal histology were investigated. The acute effects of tempol on blood pressure and TGF were studied in rats. 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-type (-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-type were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis [DeltaP(SF): 15.2 +/- 1.2 to 9.1 +/- 0.6 mmHg, turning point: 14.3 +/- 0.8 to 19.7 +/- 1.4 nl/min]. 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.

Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension

“…In earlier studies, hydronephrotic kidneys had increased oxidative stress (6,18), reduced nitric oxide bioavailability, and a sensitized tubuloglomerular feedback response (5,7). These changes may protect the hydronephrotic kidney from excessive pressure by reducing glomerular perfusion and filtration but might also play an important role in the development of hypertension by increasing preglomerular resistance and promote fluid and solute retention.…”

“…These observations have led to a worldwide trend towards nonoperative management in children with nonsymptomatic unilateral hydronephrosis, but the long-term physiological consequences of this new policy are unclear (4). We have previously demonstrated that experimentally induced hydronephrosis, after completed nephrogenesis, is associated with renal injuries and is causally related to hypertension in both rats (5,9) and mice (6,8). However, the potential link between congenital hydronephrosis and later development of hypertension and renal dysfunction has not been investigated.…”

Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis

“…This observation has led to a worldwide trend towards conservative management. The long-term physiological consequences of this new treatment policy are not known, but recent experimental studies have clearly shown an increased cardiovascular risk later in life [6,7,11].…”

Adenosine A1-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment

“…Adenosine, via activation of A 1 -receptors, has been demonstrated to mediate TGF responses in both rats (16,44) and mice (3,46), whereas activation of A 2 -receptors (A 2A or A 2B ) and nitric oxide (NO) release may attenuate the response (11). Elevated levels of ANG II and reactive oxygen species (ROS) may enhance TGF response and preglomerular reactivity (49,56) and have been associated with hypertension in several experimental models (5,6,34,48,56,57). There is considerable evidence for a synergistic interaction between ANG II and adenosine in the kidney (17), and this importantly contributes to regulation of the renal microcirculation (28).…”