Nitric oxide synthase in the JGA of the SHR: expression and role in tubuloglomerular feedback

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. Am J Physiol Renal Physiol 294: F362-F370, 2008. First published November 21, 2007 doi:10.1152/ajprenal.00410.2007.-Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.ADMA; tubuloglomerular feedback; L-arginine; L-NAME; telemetry; blood pressure HYPERTENSION IS THE MOST COMMON chronic disorders worldwide and secondary forms of hypertension are found in 5-10% of the hypertensive population, of which most can be linked to renal disease (24). In humans, as well as in experimental models of salt-sensitive hypertension, there is a growing body of evidence pointing at a close relationship between nitric oxide (NO) deficiency and development of hypertension (37).Hydronephrosis due to obstruction at the level of the pelvicureteric junction is a common condition in children, with an incidence in newborns of ϳ1%. The obstruction is mostly partial and congenital of origin. Unilateral hydronephrosis causes salt-sensitive hypertension in both rats (5) and mice (7).The renal function in hydronephrotic animals, measured as renal blood flow and glomerular filtration rate (GFR), is rather...

Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Carlström¹,

Brown²,

Edlund³

et al. 2008

“…The L-arginine/NO pathway is upregulated in SHR, with higher vascular endothelial NOS (eNOS) and renal iNOS protein mass than in WKY rats and increased nitrate plus nitrite (NO x ) excretion directly after weaning at 3-4 wk, the so-called prehypertensive stage (146). In SHR, renal cortical and macula densa nNOS levels are increased (154), and NO production by vascular smooth muscle iNOS is enhanced (160). In the brain in SHR, the NOS system is programmed differently than in other tissues.…”

Section: Inappropriate Activation Of the Renin-angiotensin-aldosteronmentioning

confidence: 99%

Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon

Racasan¹,

Braam²,

Koomans³

et al. 2005

Racasan, Simona, Branko Braam, Hein A. Koomans, and Jaap A. Joles. Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon. Am J Physiol Renal Physiol 288: F626 -F636, 2005. First published November 16, 2004 doi:10.1152/ ajprenal.00314.2004.-The "programming hypothesis" proposes that an adverse perinatal milieu leads to adaptation that translates into cardiovascular disease in adulthood. The balance between nitric oxide (NO) and reactive oxygen species (ROS) is disturbed in cardiovascular diseases, including hypertension. Conceivably, this balance is also disturbed in pregnancy, altering the fetal environment; however, effects of perinatal manipulation of NO and ROS on adult blood pressure (BP) are unknown. In spontaneously hypertensive rats (SHR), NO availability is decreased and ROS are increased compared with normotensive Wistar-Kyoto rats, and, despite the genetic predisposition, the perinatal environment can modulate adult BP. Our hypothesis is that a disturbed NO-ROS balance in the SHR dam persistently affects BP in her offspring. Dietary supplements, which support NO formation and scavenge ROS, administered during pregnancy and lactation resulted in persistently lower BP for up to 48 wk in SHR offspring. The NO donor molsidomine and the superoxide dismutase mimic tempol-induced comparable effects. Specific inhibition of inducible nitric oxide synthase (NOS) reduces BP in adult SHR, suggesting that inducible NOS is predominantly a source of ROS in SHR. Indeed, inducible NOS inhibition in SHR dams persistently reduced BP in adult offspring. Persistent reductions in BP were accompanied by prevention of proteinuria in aged SHR. We propose that in SHR the known increase in ANG II type 1 receptor density during development leads to superoxide production, which enhances inducible NOS activity. The relative shortage of substrate and cofactors leads to uncoupling of inducible NOS, resulting in superoxide production, activating transcription factors that subsequently again increase inducible NOS expression. This vicious circle probably is perpetuated into adult life. spontaneously hypertensive rat; nitric oxide; inducible nitric oxide synthase; molsidomine; tempol; proteinuria THERE IS NOW A LARGE BODY of epidemiological data proving that environmental factors acting early in life, in particular in the intrauterine and postnatal period, correlate with chronic cardiovascular diseases. From these observations, Barker (10) developed the "programming hypothesis," which proposes that fetal adaptation to adverse environmental factors in the perinatal period results in permanent structural and physiological changes that manifest as disease in adult life. As such, fetal programming is a form of phenotypic plasticity (10), which has conveyed an evolutionary advantage in the past but now has adverse effects because of relatively rapid changes in the environment in which we live (58). An example of this may be the explosion of hyperten...

“…Enhanced tubuloglomerular feedback may contribute to high blood pressure. In animal models of genetic hypertension, tubuloglomerular feedback is enhanced (53,54), and resetting of tubuloglomerular feedback may also contribute to salt-sensitive hypertension in humans (1,23,38).…”

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confidence: 99%

Depolarization of the macula densa induces superoxide production via NAD(P)H oxidase

Liu

Garvin

Ren

et al. 2007

Liu R, Garvin JL, Ren YL, Pagano PJ, Carretero OA. Depolarization of the macula densa induces superoxide production via NAD(P)H oxidase. Am J Physiol Renal Physiol 292: F1867-F1872, 2007. First published March 6, 2007; doi:10.1152 doi:10. /ajprenal.00515.2006 Ϫ ) enhances tubuloglomerular feedback by scavenging nitric oxide at the macula densa. However, the singling pathway of O 2 Ϫ production in the macula densa is not known. We hypothesized that the increase in tubular NaCl concentration that initiates tubuloglomerular feedback induces O 2 Ϫ production by the macula densa via NAD(P)H oxidase, which is activated by macula densa depolarization. We isolated and microperfused the thick ascending limb of the loop of Henle and attached macula densa in rabbits. A fluorescent dye, dihydroethidium, was used to detect O 2 Ϫ production at the macula densa. When luminal NaCl was switched from 10 to 80 mM, a situation of initiating maximum tubuloglomerular feedback response, O 2 Ϫ production significantly increased. To make sure that the shifts in the oxyethidium/dihydroethidium ratio were due to changes in O 2 Ϫ , we used tempol (10 Ϫ4 M), a stable membrane-permeant superoxide dismutase mimetic. With tempol present, when we switched from 10 to 80 mM NaCl, the increase in oxyethidium/dihydroethidium ratio was blocked. To determine the source of O 2 Ϫ , we used the NAD(P)H oxidase inhibitor apocynin. When luminal NaCl was switched from 10 to 80 mM in the presence of apocynin, O 2 Ϫ production was inhibited by 80%. To see whether the effect of increasing luminal NaCl involves Na-K-2Cl cotransporters, we inhibited them with furosemide. When luminal NaCl was switched from 10 to 80 mM in the presence of furosemide, O 2 Ϫ production was blocked. To test whether depolarization of the macula densa induces O 2 Ϫ production, we artificially induced depolarization by adding valinomycin (10 Ϫ6 M) and 25 mM KCl to the luminal perfusate. Depolarization alone significantly increases O 2 Ϫ production. We conclude that increasing luminal NaCl induces O 2 Ϫ production during tubuloglomerular feedback. O 2 Ϫ generated by the macula densa is primarily derived from NAD(P)H oxidase and is induced by depolarization. tubuloglomerular feedback TUBULOGLOMERULAR FEEDBACK refers to a negative feedback loop between the epithelial cells of the macula densa and the vascular smooth muscle cells of the afferent arteriole. Tubuloglomerular feedback regulates distal tubular sodium load by adjusting glomerular filtration rate in response to signals received from the macula densa. When the macula densa senses a decline in the delivery of NaCl to the distal tubule, it signals the afferent arteriole to dilate, which raises glomerular capillary hydraulic pressure and glomerular filtration rate and thus increases renal tubular flow and sodium delivery to the distal tubule. Increased distal NaCl delivery constricts the afferent arteriole, lowers capillary hydraulic pressure, slows glomerular filtration rate, and diminishes tubular flow (35,56 ) (31). Enhanced tubu...