NDT Advance Access published online on June 7, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm306
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Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats
1Laboratórios de Metabolismo Hidro-Salino e and 2Bioenergética, Departamentos de Clinica Médica e Patologia Clinica, Núcleo de Medicina e Cirurgia Experimental, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
Correspondence and offprint requests to: J. A. R. Gontijo, Departamento de Clínica Médica, Faculdade de Ciências Medicas, Universidade Estadual de Campinas, 13083-100 Campinas, SP, Brazil. Email: gontijo{at}fcm.unicamp.br
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Abstract |
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Background. We have previously shown that chronic metabolic acidosis, induced in rats by NH4Cl feeding, leads to nephron hypertrophy and to a decreased water-salt reabsorption by the kidneys. Since mitochondria are the main source of metabolic energy that drives ion transport in kidney tubules, we examined energy-linked functions (respiration, electrochemical membrane potential and coupling between respiration and ADP phosphorylation) in mitochondria isolated from rat kidney and liver at 48 h after metabolic acidosis induced by NH4Cl.
Methods. Mitochondria isolated from the kidneys and liver of metabolic acidotic rats, induced by NH4Cl, was used to study of the oxygen consumption by Clark-type electrode, mitochondrial electrical transmembrane potential estimated by the safranine O method and the variations in free medium Ca2+ concentrations examined by absorbance spectrum of Arsenazo III set at the 675–685 nm wavelength pair.
Results Whole kidney and liver mitochondria isolated from 48 h acidotic rats presented higher resting respiration, lower respiratory control and a lower ADP/O ratio than controls. These differences in mitochondrial coupling, between respiration and oxidative phosphorylation (ATP synthesis), were totally corrected when experiments were carried out in the presence of carboxyatractyloside, GDP and BSA, indicating that mitochondrial uncoupling proteins are more active in acidotic rat kidneys. Interestingly, determination of Ca2+ transport demonstrated a faster rate of initial Ca2+ uptake by acidotic kidney mitochondria, which resulted in a lower concentration of extra-mitochondrial Ca2+ under steady-state conditions (Ca2+ set point) when compared with control mitochondria. In contrast, there were no significant differences in the rates of Na+ or ruthenium red induced Ca2+ efflux.
Conclusions. We suggest that the mild uncoupling and higher Ca2+ accumulation represents an adaptation of the mitochondria to cope with conditions of oxidative stress and high cytosolic Ca2+, which are associated with a decreased efficiency of oxidative phosphorylation that may explain, at least in part, the striking natriuresis observed under chronic acidosis. Finally, there were no changes in Ca2+ transport or coupling in liver mitochondria isolated from the acidotic rats.
Keywords: kidney mitochondria; NH4Cl-induced metabolic acidosis; oxidative phosphorylation; respiration; uncoupling
Received for publication: 23.11.06
Accepted in revised form: 23. 4.07
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