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.

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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