Project 456703

NKCC2 operates with other transporters in the kidney to reabsorb or excrete salt and water in appropriate quantities. Importantly, high blood pressure (or hypertension) is known to develop when the kidney retains excessive amounts of salts and low sodium concentration (or hyponatremia) in the body when the kidney retains excessive amount of water. Hypertension is a major risk factor for cardiovascular diseases and hyponatremia can be deleterious to neurons in the brain. To date, three main types of NKCC2 have been identified in the kidney. Those that are of interest to us are called "A", "F" and "B". Interestingly, these different types (or variants) are not present in the exact same locations in the kidney and they appear to assume different functions. For instance, "A" could be more important in controlling water reabsorption/excretion, "F" in controlling salt reabsorption/excretion and "B" in controlling renal blood circulation. Diuretics such as Lasix (which are used in the treatment of fluid overload, certain forms of hypertension and hyponatremia) exert their effect by blocking NKCC2, but they act on all three variants indiscriminately and cause several side-effects for this reason. We believe that great benefits could be derived from the inhibition of a single variant at a time not only to improve drug tolerance, but also to obtain more precise effects. For instance, blocking "A" could be useful in preventing water retention, "F" in preventing salt retention and "B" in improving renal blood circulation. The purpose of this proposal is to study: 1) the role of each variant in great detail through animal models in which only one of the variants is missing and 2) the structure of these variants to determine whether certain regions could be targeted by specific drugs eventually. A refined knowledge of how NKCC2 works in the kidney could lead to the identification of well-tolerated interventions to halt the progression of many clinical disorders.