High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension

Abstract

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

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

“…Both left and right kidneys were therefore exposed to an identical systemic neurohormonal and metabolic environment, but controlled levels of RPP within the left kidney protected it from the high pressure. 38 Similarly to previous data, 38 we observed significantly lower renal damage in the controlled organs as measured by glomerular injury scoring ( Figure 5, D and E). As shown by immunohistochemistry, b-ENaC expression was increased in the uncontrolled kidneys compared with the controlled left kidneys ( Figure 5, A and C).…”

“…38,62 In short, rats were instrumented with indwelling arterial (right carotid artery and left femoral artery) and venous (left femoral vein) catheters. An inflatable silastic vascular occluder was implanted around the aorta between the right and left renal artery branches and exteriorized with flexible Tygon tubing at the back of the neck.…”

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

“…47 These alterations in zonal hemodynamics within the kidney may be able to explain the observation that glomerular sclerosis is seen primarily in the juxtamedullary nephrons in SHR, despite the fact that whole kidney autoregulation is well preserved and the degree of total renal damage is much less than that seen in other hypertensive models, such as in Ang II-induced hypertension and Dahl salt-sensitive hypertensive rats. [48][49][50][51][52][53] The study of Mori et al 34 in Ang II-induced hypertension gives a strong support to the concept that hypertension itself causes tissue injuries primarily in the juxtamedullary cortex and outer medulla. Using the servo-control method, they kept perfusion pressure to the left kidney at a normotensive level, while inducing systemic hypertension by intravenous infusion of Ang II.…”

“…62 When the juxtamedullary glomeruli are injured by hypertension, the impairment of oxygen delivery downstream from the vasa recta vessels would be expected to result in tubulointerstitial injuries in the outer medulla. Superimposed on these factors, a number of other elements, including neurohormonal factors, 56 inflammatory pathways, 53 oxidative stress 63,64 and tubular transport, 65,66 are involved in the pathogenesis of the injuries, among which tubulovascular crosstalk is of particular interest. 63,64,67,68 We have recently shown that an increase in tubular transport at the mTAL enhances superoxide production and reduces nitric oxide synthesis.…”

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

“…hypertension; angiotensin II; nitric oxide; inflammation; oxidative stress THE PROGRESSION OF RENAL DAMAGE varies widely among hypertensive populations (10,17,36,43) as well as in experimental models of hypertension (2, 29). While elevated blood pressure (BP), per se, clearly plays a dominant role in the progression of renal injury in many forms of hypertension (2,25,29), it is also understood that renal injury continues to worsen in some individuals despite optimal BP control (10,17,45). Several such BP-independent mechanisms have been proposed and are thought to directly contribute to renal injury and/or alter the susceptibility to BP-induced renal injury and broadly include genetic-, dietary-, and neurohumoral-related mechanisms.…”