Succinate alters respiration, membrane potential, and intracellular K+ in proximal tubule

Succinate, a dicarboxylic acid, is an intermediate in the Krebs cycle that is transported and metabolized by the renal proximal tubule. It is also known to increase proximal tubule transport of phosphate and glucose but not fluid by unknown mechanisms. In the present study, succinate increased proximal tubule respiration in a dose-dependent manner, and a kinetic evaluation indicated that two separate processes were activated. A lower-affinity (Km = 0.9 mM), higher-capacity stimulation (Vmax increase of 49%) was attributed to a decrease in the mitochondrial coupling efficiency. A higher-affinity process (Km = 0.012 mM) was related to an apparent increase in ATP synthesis. The apparent increase in ATP synthesis was not associated with a change in Na+-K+-ATPase activity, however, but rather indicated a 49% increase in ion transport-independent ATP utilization. Basolateral membrane potential hyperpolarized by -7 mV in the presence of succinate, and this was related to an increase in the K+ transference number. Finally, 1 and 5 mM succinate promoted a net cellular uptake of K+, leading to an 11% increase in intracellular K+, which was not the result of an increase in Na+-K+-ATPase activity. Thus the cellular entry and metabolism of succinate promotes multiple changes in ion transport without altering Na+-K+-ATPase activity.