Etiology of Age-Related Defects in Urine Concentration

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The ability of the kidney to concentrate and dilute urine in response to physiological demands decreases with aging in both humans and animals. The pituitary hormone arginine vasopressin (AVP) is the major regulator of renal water excretion. AVP increases water permeability in the kidney collecting duct by regulating membrane insertion and abundance of the water channel, aquaporin-2 (AP2), via vasopressin activation of the G protein-coupled AVP V2 receptor (V2R). Previous studies have shown that AVP secretion is increased rather than decreased with aging, suggesting that the age-related defect in urinary concentrating ability resides in the kidney. We hypothesize that a significant contributing mechanism to age-related impairments in urine concentration and dilution is a decreased renal responsiveness to circulating AVP, with subsequent reduced ability to adapt to changes in water balance. We plan to test this hypothesis by studying young (6 month) and old (24 month) Fischer rats to determine if adaptive changes in renal AVP V2 receptor and AQP-2 expression and function are reduced in old captured to young rats subjected to a series of physiological perturbations of fluid and electrolyte balance. These include: 1) decreased extracellular fluid water (dehydration, Aim 1); 2) increased extracellular fluid water (water loading, Aim 2); and 3) altered dietary sodium intake (low, normal, and high NaCl diet, Aim 3). In these studies, AVP V2 receptor expression will be a measured using a novel iodinated V2 receptor antagonist and by Northern analysis. AQP2 expression will be measured by Western and Northern analysis. AVP secretion will also be measured by radioimmunoassay to correlate with the V2R and AQP2 results. These studies will provide insight into the molecular mechanisms underlying functional renal senescence by identifying which part of the pathway from V2R to AQP2 may be responsible for the observed impaired renal concentrating and diluting abilities observed in rats as a function of aging. These results, and the subsequent future studies deriving from them, should therefore allow a better understanding of the fluid and electrolyte abnormalities so frequently seen in elderly individuals, and lead to a more enlightened approach to prevention and therapy of these disorders.