Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine.
Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.
de Cavanagh
Elena M V
EM
Physical-Chemistry Department, School of Pharmacy and Biochemistry, University of Buenos Aires, Helguera 2365, Buenos Aires 1417, Argentina.
Toblli
Jorge E
JE
Ferder
León
L
Piotrkowski
Bárbara
B
Stella
Inés
I
Inserra
Felipe
F
D000199:Actins / Q000032:analysis; D017311:Amlodipine / Q000494:pharmacology* / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D003576:Electron Transport Complex IV / Q000378:metabolism; D005920:Glomerular Mesangium / Q000737:chemistry / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007473:Ion Channels; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013482:Superoxide Dismutase / Q000378:metabolism; D000071246:Uncoupling Protein 2
D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D017311:Amlodipine; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D005978:Glutathione; D019808:Losartan