Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

Abstract

Abstract-Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N G -nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (Ϫ6%) but reduced it in control (Ϫ12%) and contralateral arterioles (Ϫ43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (Ϫ18%) than in control (Ϫ42%) and contralateral arterioles (Ϫ49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (Ϫ19%) compared with control (Ϫ8%) and contralateral kidneys (Ϯ0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (Ϫ40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension. Key Words: angiotensin II Ⅲ L-NAME Ⅲ oxidative stress Ⅲ NO synthase Ⅲ superoxide dismutase Ⅲ tubuloglomerular feedback H ydronephrosis because of uretero-pelvic junction obstruction is a common condition in newborns, with an incidence of Ϸ1%. Both rats and mice with hydronephrosis, because of chronic partial ureteral obstruction, develop renal injury 1 and salt-sensitive hypertension 2,3 that can be attenuated by relief of the obstruction. 4 The mechanisms are thought to be associated with increased activity of the renin-angiotensin system, 2 increased oxidative stress, and reduced NO availability in the diseased kidney. 5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hyperte...

SOD1 deficiency causes salt sensitivity and aggravates hypertension in hydronephrosis

“…Studies in isolated and perfused afferent arterioles have shown that the NO availability is reduced in SOD1-ko compared with that of SOD1-tg mice. Furthermore, hydronephrotic wild-type mice have a reduced NO production in the partially obstructed kidney (5). In the present study, the TGF reactivity and sensitivity were increased in the hydronephrotic kidney.…”

“…Chronic partial unilateral ureteral obstruction causes renal injury and salt-sensitive hypertension in both rats (7) and mice (8). Reduced nitric oxide (NO) availability in the diseased kidney, increased afferent arteriolar resistance, and resetting of the tubuloglomerular feedback (TGF) mechanism, have important roles in the development of hypertension (4,5). The cause of NO-deficiency in hydronephrosis is not clear, but oxidative stress in the diseased kidney has been suggested (5).…”

“…On the basis of earlier observations (4,5,7), it was hypothesized that renal NO deficiency and subsequent hypertension was a consequence of increased oxidative stress in the diseased kidney. Blood pressure, renal excretion of fluid, electrolytes, and 8-iso-prostaglandin-F 2␣ (F2-IsoPs) and proteins were measured continuously, and the renal histology was examined in SOD1-transgenic (SOD1-tg), knock-out (SOD1-ko), and wild-type mice.…”

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.…”

Effects of enalapril and sodium depletion on the renin-angiotensin system in hydronephrotic mice

“…There have also been a number of studies of the effect of sodium on renin release, but the mechanism by which sodium affects renin secretion is still unclear (Carlström et al 2008;Harding et al 2000;Taugner et al 1988;Tojo et al 2006;Trachte et al 2007). Most studies support the concept that renin secretion is regulated by the alternation in concentration of sodium chloride at the macula densa (Bührle et al 1986;Hackenthal et al 1990;Nobiling et al 1991;Waanders et al 2009.…”