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(Hypertension. 1998;31:266.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Nitric Oxide Synthase Activity and Renal Injury in Genetic Hypertension

Hiroshi Hayakawa; Leopoldo Raij

From the Department of Medicine, Veterans Affairs Medical Center and University of Minnesota Medical School, Minneapolis, Minnesota.

Correspondence to Leopoldo Raij, MD, VA Medical Center, Nephrology/Hypertension Section, III j, 1 Veterans Drive, Minneapolis, MN, 55417. E-mail: raijx001{at}maroon.tc.umn.edu

	Abstract

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Nitric oxide (NO) is an endogenous vasodilator synthesized in the endothelium by constitutive NO synthase (cNOS). We have shown that upregulation of cNOS activity in hypertension may contribute to forestalling left ventricular and aortic hypertrophy (Hypertension. 29: 235, 1997). NO has been shown to inhibit growth-related responses affecting vascular smooth muscle, and mesangial cells, as well as reduce production of extracellular matrix in response to injury. Here, we investigated the relationship between renal cNOS activity (conversion of [¹⁴C] L-arginine to [¹⁴C] L-citrulline) and glomerular (GIS) and tubulointerstitial (TIS) injury scores and urinary protein excretion, indices of renal injury, in age and blood pressure matched spontaneously hypertensive rats (SHR, SBP 220±9 mm Hg) fed 0.5% NaCl diet and Dahl salt-sensitive (DS) rats fed 4% NaCl diet (DS-4%, SBP 228±8 mm Hg) as well as their normotensive counterparts Wistar Kyoto rats fed 0.5% NaCl diet (WKY, 137±3 mm Hg) and DS rats fed 0.5% NaCl diet (DS-0.5%, SBP 135±4 mm Hg). In SHR, renal medullary cNOS activity was 89% higher than in WKY (8.91±0.98 vs 4.71±0.37 nmol/min/g protein, P<0.05) whereas, in hypertensive DS-4% rats cNOS activity was 43% lower than in DS-0.5% rats (1.98±0.16 vs 3.48±0.29 nmol/min/g protein, P<0.05). Renal cortical cNOS was lower than in medulla but similar in all groups; inducible NOS activity was not detected. Despite hypertension of similar severity and duration, hypertensive DS-4% developed 9 fold more GIS (190±42 vs 21±11), 20 fold more TIS (4.0±0.7 vs 0.2±0.3), and 5 fold more proteinuria (54±11 vs 8.5±3.0 mg/day), all P<0.05. The current studies, in conjunction with our recent studies in heart and aorta, strongly suggest that in hypertension, increased cNOS activity may provide a protective homeostatic role in all the end-organs that are targets of hypertensive injury.

Key Words: nitric oxide synthase • rats, inbred, SHR • rats, Dahl • hypertension • glomerular injury • renal tubulo-interstitial injury • salt sensitivity

Abbreviations: ACh = acetylcholine • cNOS = constitutive nitric oxide synthase • DS = Dahl salt-sensitive rat • DR = Dahl salt-resistant rat • GIS = glomerular injury score • LNAME = N^G-nitro-L-arginine methyl-ester • NO = nitric oxide • NOS = nitric oxide synthase • RMBF = renal medullary blood flow • SBP = systolic blood pressure • SHR = spontaneously hypertensive rats • TIS = tubulointerstitial injury score • UproV = urinary protein excretion per day • PAS = periodic acid Schiff • HE = hematoxylin and eosin • WKY = Wistar-Kyoto rats

	Introduction

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Nitric oxide (NO) is an endogenous vasodilator synthesized in the endothelium by constitutive NO synthase (cNOS). We have shown that upregulation of cNOS activity in hypertension may contribute to forestalling left ventricular and aortic hypertrophy.¹ NO has been shown to inhibit growth-related responses affecting vascular smooth muscle and mesangial cells, as well as reduce production of extracellular matrix in response to injury.^2,3

NO is released from vascular endothelial cells in response to a variety of stimuli.^2–6 NO is also reported to modulate blood flow and pressure-natriuresis in the kidney.^7–9 Administration of the inhibitor of NO synthesis N^G-nitro-L-arginine methylester (LNAME) decreases renal blood flow and sodium excretion without affecting the glomerular filtration ratio.¹⁰ In vivo, administration of N^G-nitro-L-arginine abolishes acetylcholine (ACh)-induced increase in renal papillary blood flow and sodium excretion.⁸ These studies suggest that NO may play an important role in the regulation of blood pressure through alterations in renal medullary blood flow.

The present study was undertaken to investigate the relationship between renal cNOS activity (conversion of [¹⁴C] L-arginine to [¹⁴C] L-citrulline) and glomerular (GIS) and tubulo-interstitial (TIS) injury scores and urinary protein excretion, indices of renal injury in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats matched for severity and duration of hypertension.

	Materials and Methods

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Materials
SHR and Wistar-Kyoto (WKY) rats were purchased from Taconic Farms (Germantown, NY). Male DS rats and Dahl salt-resistant (DR) rats from the Brookhaven strain were purchased from Harlan Sprague Dawley (Indianapolis, Ind). [¹⁴C] L-arginine was purchased from Amersham International. Dowex resin (AG50WX-8, H⁺ form) was purchased from Bio-Rad Laboratories. Other chemicals used were purchased from Sigma Chemical.

Experimental Animals
Seven-week-old DS and DR rats were fed standard rat chow that contained either 4% NaCl (DS-4.0%: n=7 and DR-4.0%: n=7) or 0.5% NaCl (DS-0.5%: n=7 and DR-0.5%: n=7) for 8 weeks. DS and DR groups were used for the experiments at the age of 16 weeks. SHR (n=7) with similar hypertension to DS-4.0% and age-matched WKY rats (n=7) were used for experiments at 16 weeks of age. Both SHR and WKY rats were fed standard rat chow that contained 0.5% NaCl. All rats had free access to water and were housed 5 per cage in facilities accredited by the American Association for Accreditation of Laboratory Animal Care. The animal studies were approved by the Institutional Animal Care and Use Committee.

Systolic blood pressure (SBP) was measured by a tail-cuff method;⁴ 24-hour urine excretion was obtained in metabolic cages as previously described. Urine protein concentration was determined using BioRad protein assay kit and expressed in mg/24 hr (UproV).

Determination of NOS activity in renal medulla and aorta
cNOS activity was measured in the renal medulla and cortex as well as in the thoracic aorta of each rat. Left kidneys and thoracic aortas were excised from rats and frozen in liquid nitrogen and stored at -80°C until use. The kidneys were carefully separated into medulla and cortex before freezing. Tissues were homogenized in 3 volumes of ice-cold buffer solution containing 50 nmol/L Tris-HCl (pH 7.4), 0.1% mercaptoethanol, 1% Triton-X, 0.1 mmol/L EDTA, 0.1 mmol/L EGTA, 2 µmol/L leupeptin, 1 µmol/L pepstatin A, 1 mmol/L phenylmethylsulfonyl fluoride using a Omni TH homogenizer (Omni International). The homogenates were centrifuged at 20,000g for 45 minutes. The supernatants were used for measuring NOS activity and protein concentration.

The conversion of [¹⁴C] L-citrulline from [¹⁴C] L-arginine by NOS was measured in the supernatants from tissues, as described previously.¹ Briefly, 40 µl of the supernatant was added to 100 µl of assay buffer containing 50 mmol/L KH₂PO₄, 1 mmol/L MgCl₂, 1 mmol/L CaCl₂, 50 mmol/L valine, 1 mmol/L L-citrulline, 20 µmol/L L-arginine, 1 mmol/L DTT, 2 mmol/L NADPH, 3 µmol/L tetrahydro biopterin, 3 µmol/L flavin adenine dinucleotide, 3 µmol/L flavin mononucleotide, and 0.5 µCi/ml L-[¹⁴C] arginine HCl. The mixture of supernatant and assay buffer solution was incubated for 20 minutes at 37°C in the presence or absence of either EGTA (1 mmol/L) or EGTA (1 mmol/L)+L-nitro arginine (1 mmol/L) to determine the contribution of the Ca²⁺-dependent (cNOS) and Ca²⁺-independent (inducible NOS) to the total activity. After the incubation, the reaction was stopped by adding 500 µL of ice-cold solution containing 20 mmol/L Hepes, 2 mmol/L EDTA, 2 mmol/L EGTA. The incubated mixture was loaded on to 1-mL columns of Dowex resin (Na⁺ form) and the columns were then eluted with 500 µL of distilled water. The amount of [¹⁴C]L-citrulline was determined with a liquid scintillation counter. NOS activity was expressed as nanomols of [¹⁴C]L-citrulline formed per gram of protein per minute.

Renal Histology
The right kidney was fixed in buffered formalin and stained with hematoxylin and eosin (HE) and periodic acid Schiff (PAS). Histological evaluation of kidney coronal sections was performed by one of the authors (LR) in a blinded fashion. The glomerular injury was evaluated using a semiquantitative scoring method described previously.¹¹ Briefly, the severity of the glomerular lesion was graded from 0 to 4+ according to the percentage of glomerular involvement. The GIS was calculated by summing the products of the severity score and the percentage of glomeruli displaying the same degree of severity.¹¹ Tubulointerstitial injury was also determined. Briefly, the severity of the tubular dilation, interstitial fibrosis, and mononuclear cell infiltration were graded semiquantitatively from 0 to 5+ in an average of 3 to 5 fields per kidney coronal section.

Calculations and Statistical Analysis
Results of the experiments are given as mean±SEM. Statistical analysis was performed by ANOVA (Statview) among groups and by unpaired t test between WKY rats and SHR. Significance was assumed at P<0.05.

	Results

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SBP at the age of 16 weeks is shown in the table. SHR showed significantly higher SBP than WKY rats. SBP in DS-4.0% rats was higher than that in the normotensive control (DS-0.5%). No difference in SBP was found among DR-4.0%, DR-0.5%, and DS-0.5% rats, all of which remained normotensive throughout the study. SBP was similar in hypertensive SHR and DS-4.0% rats (220±9 vs 228±8 mm Hg, respectively, P: ns). DS-4% rats developed marked cardiac and renal hypertrophy compared with normotensive DS-0.5%, DR-4%, or DR-0.5% rats. However, SHR did not develop renal hypertrophy, and manifested minimal ventricular hypertrophy (Table 1).

View this table: [in this window] [in a new window]   Systolic Blood Pressure (SBP), Body Weight (BW), Kidney Weight (KW) and Ventricular Weight (VW) in WKY, SHR, and Dahl rats

cNOS activity in the medulla of SHR was increased 89% compared to that in WKY (P<0.05, n=6–7, Fig 1). In the cortex, cNOS activity was less than in medulla in both WKY and SHR. Different from the medulla, cNOS activity was similar in the cortex of WKY and SHR (P: ns). Figure 2 shows cNOS activity in medulla and cortex of DS rats. In contrast to SHR, and despite similar duration and severity of SBP, hypertensive DS-4% showed a 43% decrease in cNOS activity in the medulla compared with normotensive DS-0.5% rats (P<0.05, n=6–7). In DR rats, high dietary NaCl did not affect cNOS activity in either medulla (DR-0.5%: 1.61±0.06 vs DR-4%: 1.96±0.22 nmol/min/g protein, P: ns, n=6) or cortex (0.60±0.09 vs 0.67±0.06 nmol/min/g protein, P: ns). Similar to WKY and SHR in DS rats, cNOS activity in cortex was less than that in medulla.

View larger version (30K): [in this window] [in a new window]   Figure 1. cNOS activity in the renal medulla and cortex of WKY rats and SHR (n=6–7). cNOS activity was determined by conversion of [14C] L-arginine to [14C] L-citrulline. *P<0.05 vs WKY rats. Values are mean±SE.

View larger version (29K): [in this window] [in a new window]   Figure 2. cNOS activity in the renal medulla and cortex of DS-0.5% and DS-4% rats (n=6–7). cNOS activity was determined by conversion of [14C] L-arginine to [14C] L-citrulline. *P<0.05 vs DS 0.5% rats. Values are mean±SE.

In the thoracic aorta, cNOS activity was increased 133% in hypertensive SHR compared with normotensive WKY rats (P<0.05, n=6, Fig 3). On the other hand, hypertensive DS-4% rats had 70% lower cNOS activity than normotensive DS-0.5% rats (P<0.05, n=6, Fig 4). Aortic cNOS activity was similar in DR-4% and DR-0.5% rats (P: ns). No significant activity of Ca²⁺-independent NOS was found in either the aorta or the kidneys of rats from any of the groups.

View larger version (33K): [in this window] [in a new window]   Figure 3. cNOS activity in the thoracic aortae of WKY rats and SHR (n=6). cNOS activity was determined by conversion of [14C] L-arginine to [14C] L-citrulline. *P<0.05 vs WKY rats. Values are mean±SE.

View larger version (44K): [in this window] [in a new window]   Figure 4. cNOS activity in the thoracic aortae of Dahl rats (n=6). cNOS activity was determined by conversion of [14C] L-arginine to [14C] L-citrulline. *P<0.05 vs DS-0.5% rats, DR 0.5% and DR 4%. Values are mean±SE.

Hypertensive DS-4% rats showed 5 fold more proteinuria than SHR (P<0.05, n=6–7, Fig 5A) and 9 fold more glomerular injury (P<0.05, n=6–7, Fig 5B). Furthermore, tubulointerstitial injury in DS-4% rats was 20 fold more severe compared with similarly hypertensive SHR (P<0.05, n=6–7, Fig 5C). Tubulointerstitial injury affected the whole kidney but it was more severe in the juxtamedullary and medullary region. Normotensive control rats: WKY, DS-0.5%, DR-4%, or DR-0.5% rats, did not show significant proteinuria, glomerular, or tubulointerstitial injury.

View larger version (24K): [in this window] [in a new window]   Figure 5. Renal injury was evaluated by determining (A) urinary protein excretion, (B) glomerular injury score, and (C) tubulointerstitial injury score, in hypertensive SHR and DS-4% rats. *P<0.05 vs SHR. Values are mean±SE.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
It has been documented that endothelium-dependent vasorelaxation is attenuated in populations of hypertensive humans^12,13 and in several animal models of hypertension.^{1,4,6,14–16} Endothelium-dependent relaxation mediated by NO is reduced in the thoracic aorta of DS rats but is preserved in SHR, although in the latter, it is obscured by the concomitant synthesis of endothelium derived contracting factors.^15,17 Hayakawa et al reported that, in the kidney, vascular relaxation in response to ACh was attenuated in hypertensive SHR, DS, and deoxycorticosterone acetate (DOCA) rats. However, NO release was decreased in kidneys of DS and DOCA rats, whereas, it was increased in kidneys of SHR.^6,14,16,18 Furthermore, we recently showed that, compared with their normotensive counterparts, cNOS activity in the thoracic aorta is reduced in DS rats, but it is increased in SHR.¹

It has been suggested that alteration in the pressure-natriuresis relationship influences the long-term control of systemic arterial pressure.^19–20 Some but not all investigators subscribe to the concept that regulation of renal medullary blood flow (RMBF) plays an important role in the maintenance of homeostatic pressure-natriuresis.^19–20 In animals, administration of NO-dependent vasodilators, such as ACh, increases RMBF accompanied by natriuresis and diuresis.^9,20,21 On the other hand, direct renal medullary infusion of an cNOS inhibitor results in decreased papillary blood flow and sodium excretion.⁸ In the present study, we demonstrated that cNOS activity in the renal medulla of hypertensive DS rats was decreased compared with normotensive DS rats and that these changes in medullary NOS activity were linked to hypertension and not with the amount of salt intake, since DR rats fed high dietary salt maintained steady levels of renal cNOS. However, excess dietary NaCl may aggravate hypertensive vascular injury. The findings in the current studies are commensurate with the notion that in DS rats the fall in medullary NOS activity is a maladaptive response that could contribute to the maintenance of hypertension.^19–20 DS rats not only developed glomerular injury, but also showed severe tubulointerstitial disease and marked renal hypertrophy. There is substantial evidence supporting the notion that NO inhibits vascular smooth muscle and mesangial cell hypertrophy/hyperplasia as well as extracellular matrix production, driven by growth factors such as PDGF and TGFß, which are activated during tissue injury.^2,3 Hence, it is reasonable to assume that severe tubulointerstitial disease in DS rats is in part due to local NO deficiency. Furthermore it has been reported that chronic NOS inhibition leads to glomerular, tubular and interstitial injury.²² These findings are important because clinically, progression of renal failure correlates better with tubulointerstitial disease than with glomerular disease.^23,24

We found that similar to what we have previously observed in the heart and aorta, SHR rats upregulate cNOS activity in renal medulla. Increased cNOS activity fails, however, to prevent hypertension in SHR, likely because SHR have concomitant increases in endothelium dependent and independent contracting factors.^15,17 In previous studies we demonstrated that in SHR upregulation of cNOS in the heart and in the aorta was inversely correlated with cardiac and aortic hypertrophy as well as with the severity of hypertension.¹ In the current studies, increased cNOS activity in the renal medulla of SHR is accompanied by a remarkable absence of tubulointerstitial disease and minimal renal hypertrophy. Interestingly, NOS inhibition leads to not only glomerular and arteriolar sclerosis but also severe tubulointerstitial changes in SHR.²²

We have previously demonstrated that at similar levels of systemic hypertension DS, but not SHR rats develop glomerular injury and that these differences in glomerular pathology occur because DS but not SHR develop glomerular hypertension.²⁵ In the current studies we failed to demonstrate differences in cNOS activity in the renal cortex between SHR and DS rats and their respective normotensive counterparts. However, we must be cautious in interpreting these results, given that the amount of cNOS activity present in renal cortex is very low and therefore the differences between groups may be small and beyond the sensitivity of our current technology.

In the present study, the assay method for cNOS activity that we used is not able to discriminate the specific localization of cNOS activity in the cortex and medulla. However, Ujiie et al demonstrated that cNOS mRNA was expressed at high level in vasculature and inconsistently in proximal tubules, thick ascending limbs, and collecting duct.²⁶ In addition, Terada et al showed expression of cNOS in glomerulus, renal tubules, and the vascular system using PCR.²⁷ We speculate that in our studies most of cNOS activity comes from renal vasculature, and a portion of the enzyme activity may originate from renal tubules.

Clinical studies have suggested that in hypertensive humans’ endothelial dysfunction may not be a universal finding.^12,13,28 Furthermore, the prevalence of renal failure, left ventricular hypertrophy, and stroke that are major causes of morbidity and mortality varies between 10% and 40% in different populations of hypertensives.^29,30 Moreover, in patients with end stage renal failure, the prevalence of coronary artery disease and left ventricular hypertrophy is dramatically higher than in populations of patients with similar severity of hypertension.³¹ Based upon clinical and experimental data, including the current studies, we hypothesize that vascular cNOS activity in response to hypertension may be heterogeneous and conditioned by genetic and environmental factors. We further hypothesize that these differences in cNOS activity in response to hypertension may explain, at least in part, the variations in end-organ disease observed in humans with hypertension of similar severity.

	Acknowledgments

 
This study was supported with funds from the Department of Veterans Affairs. H Hayakawa was supported with funds from Ueda Memorial Trust Fund for Research of Heart Disease. We express our thanks to Karen Coffee for her technical assistance and Barb Devereaux for secretarial support.

Received September 17, 1997; first decision October 10, 1997; accepted October 24, 1997.

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