Abstract
Oxygen tension in the kidney is mostly determined by O(2) consumption (Qo(2)), which is, in turn, closely linked to tubular Na(+) reabsorption. The objective of the present study was to develop a model of mitochondrial function in the proximal tubule (PT) cells of the rat renal cortex to gain more insight into the coupling between Qo(2), ATP formation (G(ATP)), ATP hydrolysis (Q(ATP)), and Na(+) transport in the PT. The present model correctly predicts in vitro and in vivo measurements of Qo(2), G(ATP), and ATP and P(i) concentrations in PT cells. Our simulations suggest that O(2) levels are not rate limiting in the proximal convoluted tubule, absent large metabolic perturbations. The model predicts that the rate of ATP hydrolysis and cytoplasmic pH each substantially regulate the G(ATP)-to-Qo(2) ratio, a key determinant of the number of Na(+) moles actively reabsorbed per mole of O(2) consumed. An isolated increase in Q(ATP) or in cytoplasmic pH raises the G(ATP)-to-Qo(2) ratio. Thus, variations in Na(+) reabsorption and pH along the PT may, per se, generate axial heterogeneities in the efficiency of mitochondrial metabolism and Na(+) transport. Our results also indicate that the G(ATP)-to-Qo(2) ratio is strongly impacted not only by H(+) leak permeability, which reflects mitochondrial uncoupling, but also by K(+) leak pathways. Simulations suggest that the negative impact of increased uncoupling in the diabetic kidney on mitochondrial metabolic efficiency is partly counterbalanced by increased rates of Na(+) transport and ATP consumption. This model provides a framework to investigate the role of mitochondrial dysfunction in acute and chronic renal diseases.