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Angiotensin II AT1 receptor blockade improves renal perfusion in hypercholesterolemia
Alejandro R Chade1, Martin Rodriguez-Porcel, Steven J Rippentrop
1Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
Insights
Blocking the angiotensin II type 1 (AT1) receptor improved kidney blood flow and function in hypercholesterolemic pigs. This suggests the renin-angiotensin system contributes to impaired renal perfusion in high cholesterol states.
Area of Science:
- Nephrology
- Cardiovascular Science
- Pharmacology
Background:
- Hypercholesterolemia (HC) is a known risk factor for kidney disease.
- HC may activate the angiotensin II type 1 (AT1) receptor, accelerating renal damage.
- Diet-induced HC impairs renal perfusion, but AT1 receptor involvement is unclear.
Purpose of the Study:
- To test if AT1 receptor blockade improves renal perfusion and function in hypercholesterolemic pigs.
- Investigate the role of the AT1 receptor in diet-induced hypercholesterolemia-related renal dysfunction.
Main Methods:
- Electron beam computed tomography quantified renal hemodynamics and function in pigs.
- Pigs were fed normal, HC, or HC + irbesartan (AT1 antagonist) diets for 12 weeks.
- Vasoactive challenges (acetylcholine, sodium nitroprusside) assessed responses.
Main Results:
- Basal perfusion and tubular function were similar across groups.
- Hypercholesterolemic pigs showed blunted cortical perfusion and altered tubular responses.
- AT1 receptor blockade normalized cortical perfusion and tubular function, reducing oxidative stress markers.
Conclusions:
- AT1 receptor blockade in hypercholesterolemia improves renal perfusion and tubular function.
- This improvement is linked to reduced oxidative stress.
- Suggests the renin-angiotensin system's role in HC-related renal impairment and potential therapeutic benefits of AT1 blockers.
Background:
Hypercholesterolemia (HC) is a risk factor for renal disease that may activate the angiotensin II type 1 (AT1) receptor and accelerate renal damage. Early diet-induced HC impairs renal perfusion responses, but it is yet unknown whether the AT1 receptor is involved. This study tested the hypothesis that AT1 receptor blockade improved renal perfusion and functional responses in hypercholesterolemic pigs.
Methods:
Regional renal hemodynamics and function in vivo were quantified bilaterally in pigs, at baseline and during vasoactive challenge (acetylcholine or sodium nitroprusside), using electron beam computed tomography after 12 weeks of normal (n = 6) or HC diet (n = 6), or HC diet supplemented (100 mg/d) with the AT1-receptor antagonist irbesartan (HC + AT1, n = 6).
Results:
Basal cortical and medullary perfusion was similar among the groups. Basal tubular function was similar on normal and HC diets, whereas HC + AT1 showed decreased proximal and distal fluid reabsorption. Hypercholesterolemic pigs had blunted cortical perfusion (P = .22) and augmented tubular responses to acetylcholine, whereas on HC + AT1 diet, cortical perfusion (P = .002) and tubular function were similar to normal animals. This was associated with decreased systemic levels of the oxidative stress markers thiobarbituric acid reactive substances.
Conclusions:
The AT1 receptor blockade in HC improves renal perfusion and tubular functional responses to endothelium-dependent vasodilators, in association with a decrease in oxidative stress. These results imply involvement of the renin-angiotensin system in the blunted renal cortical perfusion responses observed in HC, and suggest a potential role for these agents in preservation of intrarenal hemodynamics and function in HC.