Combination of Hypercholesterolemia and Hypertension Augments Renal Function Abnormalities

Abstract

Abstract-Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (nϭ10) or hypercholesterolemic (nϭ10) diet, renovascular hypertension (nϭ7), or combined hypercholesterolemiaϩhypertension (nϭ6). The hypercholesterolemic and hypercholesterolemicϩhypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemicϩhypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6Ϯ4.7%, Pϭ0.002) but not in hypercholesterolemic or hypertensive animals (8.0Ϯ7.4% and 8.2Ϯ5.9%, respectively; PϾ0.05). Moreover, in the hypercholesterolemicϩhypertensive group, cortical perfusion response was further attenuated (2.5Ϯ4.8%, Pϭ0.02) and significantly different from the group fed a normal diet (PϽ0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemicϩhypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemiaϩhypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis. Clinical studies have shown that the coexistence of dyslipidemia and HT greatly increases the incidence of cardiovascular morbidity and mortality 4 and likely modulates the deterioration of renal function as well. 5 Indeed, both antihypertensive and lipid-lowering therapies can halt the progression of renovascular disease and contribute to the preservation of renal function. 6 The onset of renal injury is detectable after a relatively short exposure to cardiovascular risk factors, inasmuch as experimental HC and HT have each been linked to alterations of vascular and tubular function. We have previously shown that experimental HC was associated with alterations in the renal vascular response to challenge both in vivo 7 and in vitro 8 and abnormal tubular dynamics in vivo. 7 Similarly, HT has been shown to induce abnormalities of renal vascular 9 and tubular 10 function. One of the mechanisms...

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

“…We have previously shown in our model that a 12-week HC diet consistently did not increase blood pressure either. 8,17,25 …”

“…6 -9 Of these, 7 ani-mals were fed for 10 weeks with the HC diet and then changed over to a normal pig chow for the remaining 6 weeks (HC-N; nϭ7), whereas in the other 7, the HC diet was sustained for the entire 16 weeks (HC-HC; nϭ7). We have previously shown that a 10-to 12-week HC diet in the swine resulted in endothelial dysfunction and activation of injurious mechanisms 8,17,18 in the absence of obstructive atherosclerotic plaques in different vascular beds (eg, aorta, renal, or coronary arteries), similar to humans with early atherosclerosis. 19 An additional group of pigs fed with a normal diet for 16 weeks was used as controls (normal; nϭ7).…”

The Impact of Protein Intake on Renal Function Decline in Women with Normal Renal Function or Mild Renal Insufficiency

“…The detrimental effect of protein intake observed in studies of patients with renal disease may also be related to the fact that many sources of animal protein are high in cholesterol and saturated fat. High cholesterol levels have also been shown to be a risk factor for progression of renal disease and may adversely affect renal function and renal hemodynamics (37)(38)(39). Therefore, since dietary intake of animal fat influences serum cholesterol level, we adjusted for animal fat intake as well as hypercholesterolemia.…”

Increased hypoxia and reduced renal tubular response to furosemide detected by BOLD magnetic resonance imaging in swine renovascular hypertension

“…Eight weeks before the imaging studies, unilateral renal artery stenosis (RAS) was induced. At baseline, under sterile conditions and fluoroscopic guidance, a metal wire coil was engaged in the proximal-middle section of the right renal artery as previously described (8,9,25,33). This induces a variable reactive hypertrophy of the arterial intimal wall, resulting in different degrees of hypertension.…”