Interaction of modeling and experimental approaches to understanding renal salt and water balance

Understanding of renal function has profited greatly from quantitative and modeling approaches throughout this century. One of the most salient examples is the concentration and dilution of the urine--a fundamental characteristic of the mammalian kidney. Only in the last three decades have the necessary components of this and other renal mechanisms been confirmed at the molecular level, but there have also been surprises. For example, the high water permeability of the proximal tubule has been shown to be imparted by the water channel, aquaporin AQP1; however, genetic knockout of this water channel is at least partially compensated by intrarenal feedback mechanisms. Also, the critical role played by the fine regulation of Na+ reabsorption in the collecting duct for the maintenance of normal blood pressure presents challenges to our understanding of the integrated interaction among systems. As a first step in placing the kidney in the physiome paradigm, we need to integrate our currently restricted mathematical models, to develop accessible databases of critical parameter values together with indices of their degrees of reliability and variability, and to describe regulatory mechanisms and their interactions from the molecular to the interorgan level. However, even greater will be the challenge to anticipate, and hopefully predict, the subtle ways in which the organism typically adapts to aberrations in these normal functional parameters, but sometimes does not.