Long-term blood pressure control prevents oxidative renal injury.
Arterial hypertension is a leading contributor to the progression of chronic renal disease. Short-term studies had addressed the role of oxidative stress in hypertensive nephropathy. We have now studied oxidative stress and caspase activation in a long-term model of hypertensive renal injury. Nontreated spontaneously hypertensive rats with uninephrectomy displayed severe arterial hypertension over a 36-week follow-up. Uncontrolled high blood pressure in the context of modest renal mass reduction resulted in significant histological renal injury. Blood pressure control by the angiotensin-converting enzyme (ACE) inhibitor, quinapril, or the AT1 receptor antagonist, losartan, decreased the degree of renal injury. Hypertensive renal injury was associated with evidence of activation of the apoptotic pathway (increased activation of caspase-3) and local renal (increased staining for 4-hydroxy-2-nonenal) and systemic [increased serum levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha)] lipid oxidation when compared with normotensive control rats. In addition, severe hypertension decreased the renal antioxidant defenses, as exemplified by decreased expression of Cu/Zn superoxide dismutase. Treatment with quinapril or losartan decreased caspase-3 activation, 4-hydroxy-2-nonenal staining, and 8-iso-PGF2alpha levels and increased Cu/Zn superoxide dismutase expression. These results suggest that hypertension-associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.
Lazaro
Alberto
A
Renal and Vascular Pathology Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Gallego-Delgado
Julio
J
Justo
Pilar
P
Esteban
Vanesa
V
Osende
Julio
J
Mezzano
Sergio
S
Ortiz
Alberto
A
Egido
Jesus
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001794:Blood Pressure; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000503:physiopathology* / Q000628:therapy*; D006977:Hypertension, Renal / Q000473:pathology; D007150:Immunohistochemistry; D007668:Kidney / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress; D000077583:Quinapril; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013482:Superoxide Dismutase / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D044005:Tetrahydroisoquinolines; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D013482:Superoxide Dismutase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019808:Losartan; D000077583:Quinapril