Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in the Dahl-SS Rat

Johnson, Richard J.; Gordon, Katherine; Giachelli, Cecilia M.; Kurth, Terry; Skelton, M. M.; Cowley, Allen W.

doi:10.1097/00004872-200018100-00019

Cited by 68 publications

(65 citation statements)

References 28 publications

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“…34 Enhanced production of superoxide in this region can cause reduction in medullary blood flow and hypoxia, 36 which in turn may stimulate renal injury. It seems from this study that the development of renal injury that progresses naturally in the outer medulla of the SS rats (as shown in a previous study 37 and by the sham rats of this study) was significantly accelerated in the kidneys subjected to the elevated arterial pressure.…”

Section: Perfusion-induced Stimulation Of Renal Inflammatory Changessupporting

confidence: 78%

High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension

Mori

Polichnowski

Glocka

et al. 2008

Journal of the American Society of Nephrology

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Renal injury in the Dahl salt-sensitive rat mimics human salt-sensitive forms of hypertension that are particularly prevalent in black individuals, but the mechanisms that lead to the development of this injury are incompletely understood. We studied the impact of renal perfusion pressure (RPP) on the development of renal injury in this model. During the development of salt-induced hypertension over 2 wk, the RPP to the left kidney was maintained at control levels (125 Ϯ 2 mmHg) by continuous servocontrol inflation of an aortic balloon implanted between the renal arteries; during the same period, the RPP to the right kidney rose to 164 Ϯ 8 mmHg. After 2 wk of a 4% salt diet, DNA microarray and real-time PCR identified genes related to fibrosis and epithelial-to-mesenchymal transition in the kidneys exposed to hypertension. The increased RPP to the right kidney accounted for differences in renal injury between the two kidneys, measured by percentage of injured cortical and juxtamedullary glomeruli, quantified proteinaceous casts, number of ED-1-positive cells per glomerular tuft area, and interstitial fibrosis. Interlobular arteriolar injury was not increased in the kidney exposed to elevated pressure but was reduced in the control kidney. We conclude that elevations of RPP contribute significantly to the fibrosis and epithelial-to-mesenchymal transition found in the early phases of hypertension in the salt-sensitive rat. Rapid development of renal injury is a prominent feature of salt-induced hypertension in the Dahl salt-sensitive (SS) rat. Within a few weeks of high salt exposure, SS rats develop substantial injuries in preglomerular vessels, glomeruli, and the tubulointerstitial compartment. [1][2][3] This prominence of renal injury in the SS rat mimics human salt-sensitive forms of hypertension that are particularly prevalent in black individuals. 4 The extent of renal injury is known to vary widely in various forms of hypertension. Rapid development of renal injury in SS rats is in sharp contrast with that observed in spontaneously hypertensive rats (SHR), another commonly used rat model of hypertension. Hypertension in the SHR of a magnitude and duration similar to that seen in SS rats results in little or no renal injury. [5][6][7][8] Moreover, although it is recognized that hypertension is a strong independent risk factor for renal failure, the effectiveness of BP control in the reduction of renal injury varies greatly between subpopulations of hypertensive patients. 9 -11 These observations have clouded the question of how much physical factors related to the elevation of renal perfusion pressure (RPP) actually contribute to renal injury in hypertension. This issue has not been easily clarified given the difficulty in sustaining a chronic increase

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Section: Perfusion-induced Stimulation Of Renal Inflammatory Changessupporting

confidence: 78%

High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension

Mori

Polichnowski

Glocka

et al. 2008

Journal of the American Society of Nephrology

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“…However, it is not widely recognized that at least in certain types of hypertension considerable heterogeneities exist among different nephron populations. [31][32][33][34] Specifically, tissue injury is most obvious in the juxtamedullary region and outer medulla in spontaneously hypertensive rats (SHRs), 31 Dahl salt-sensitive hypertensive rats, 32 renovascular hypertension 33 and angiotensin II (Ang II)-induced hypertension. 34 In addition, it has been shown that in SHRs glomerular lesions first appear predominantly in the juxtamedullary nephrons and then extend toward more superficial nephrons.…”

Section: Albuminuria and Endothelial Dysfunctionmentioning

confidence: 99%

“…54 Thus, when a high concentration of Ang II is present in renal circulation, it would constrict the superficial afferent arteriole very strongly, and consequently ischemic damages would be induced irrespective of whether BP is elevated or not. For the tubulointerstitial injuries of the outer medulla seen in various hypertensive models, [32][33][34] several factors would seem to be involved. Blood flow to the renal medulla is supplied by the descending vasa recta, which emanate from the efferent arterioles of the juxtamedullary glomeruli (Figure 1).…”

Section: Albuminuria and Endothelial Dysfunctionmentioning

confidence: 99%

“…30 However, as discussed above, regardless of the pathogenesis of microalbuminuria, the anatomical sites that are injured initially or more severely are the juxtamedullary afferent arterioles and glomeruli. [32][33][34] It would be reasonable to expect that in the early stages of hypertension, diabetes or aging, renal injury occurs predominantly in the juxtamedullary nephrons, whereas the majority of other nephrons remain relatively intact. This would be expected to result in only minimal increases of urinary albumin excretion.…”

Section: Albuminuria As An Early Marker Of Strain Vessel Injuriesmentioning

confidence: 99%

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Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk

et al. 2009

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Albuminuria is closely associated with stroke and cardiovascular diseases (CVDs) as well as the salt sensitivity of blood pressure (BP). Although albuminuria may reflect generalized endothelial dysfunction, there may be more specific hemodynamic mechanisms underlying these associations. Cerebral hemorrhage and infarction occur most frequently in the area of small perforating arteries that are exposed to high pressure and that have to maintain strong vascular tone in order to provide large pressure gradients from the parent vessels to the capillaries. Analogous to the perforating arteries are the glomerular afferent arterioles of the juxtamedullary nephrons. Hypertensive vascular damage occurs first and more severely in the juxtamedullary glomeruli. Therefore, albuminuria may be an early sign of vascular damages imposed on 'strain vessels' such as perforating arteries and juxtamedullary afferent arterioles. Coronary circulation also occurs under unique hemodynamic conditions, in which the entire epicardial segments are exposed to very high pressure with little flow during systolic phases. From the evolutionary point of view, we speculate that such circulatory systems in the vital organs are mandatory for survival under the danger of hypoperfusion due to difficult access to salt and water as well as high risks of wound injuries. In addition, albuminuria would indicate an impairment of renal medullary circulation, downstream from the juxtamedullary glomeruli, and therefore an impaired pressure natriuresis, which would lead to salt sensitivity of BP. Our 'strain vessel hypothesis' may explain why hypertension and diabetes, unforeseen in the concept of evolution, preferentially affect vital organs such as the brain, heart and kidney.

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“…Mechanisms that decrease blood flow to this area of the kidney result in long-term alterations in arterial blood pressure 7 as are seen with local increases of O 2 ⅐Ϫ and H 2 O 2 in the renal medulla of Sprague Dawley rats, which causes hypertension. 8,9 Additionally, tubulointerstitial fibrosis and capillary injury occur first in the outer medulla and juxtamedullary glomeruli in many forms of experimental hypertension, including SS rats, 10 and ROS are considered to be importantly involved in the progression of kidney disease. SS rats that develop hypertension with a 4% NaCl diet exhibit increased oxidative stress in the renal medulla and significant renal damage, which can be ameliorated by antioxidants.…”

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confidence: 99%

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

et al. 2006

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Abstract-Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13 BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13 BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13 BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13 BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 g/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059Ϯ130 to 422Ϯ80 (oxyethidium fluorescence units) and mean arterial pressure from 175Ϯ4 to 157Ϯ6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13 BN . We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.

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Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in the Dahl-SS Rat

Abstract: Tubulointerstitial injury and the loss of NOS occur after birth and parallel the development of hypertension. We suggest that the structural and functional changes that occur with renal injury in the Dahl-SS rat may contribute to the development of hypertension.

Cited by 68 publications

References 28 publications

High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension

High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension

Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

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