Endothelin Effects on Renal Vascular Resistance with Age

Falcone, Jeff

Abstract

Renal function declines at a rate of 1 to 2 percent per year after age 40. This decline with age is most notable as a decrease in both renal flow (RBF) and glomerular filtration rate (GFR) brought about by increased renal vascular resistance. Endothelin (ET), a vasoconstrictor peptide, produced by the vascular endothelial cells has been implicated in the increased renal vascular resistance observed with aging. The vasoconstrictor effects of endothelin appear to be mediated by specific vascular smooth muscle receptor modulation through heterotrimeric G proteins (G alpha q and G alpha iota). Therefore we have formed the hypothesis that elevations in renal vascular resistance and reductions in RBF and GFR may be due to an increased preglomerular constrictor responsiveness to endothelin that may have its basis as increased vascular smooth muscle G alpha q activity.
Three specific aims are proposed to test the hypothesis: 1. To determine if renal microvascular responsiveness to endothelin-1 increases with age. 2. To determine if the expression of endothelin receptor subtype and endothelin production on the renal vasculature is altered during aging. 3. To investigate the cellular mechanisms responsible for the increased endothelin responsiveness with aging. A combination of in vivo, isolated arteriole and molecular techniques will be utilized to address the specific aims. We will measure the sensitivity of renal microvessels from the rat to exogenous endothelin at four ages. We will also examine if there is an upregulation of renal vascular smooth muscle ET receptors with age. We also propose to measure the amount (G protein mass) and activity (GTP to GDP binding ratios) of G alpha q/11 and G alpha iota 1-3 in renal vascular tissues at the four ages in response to ET-1. We expect to find a progressive increase in microvascular sensitivity to ET-1 with age. This increased sensitivity will probably be mediated through an upregulation or increased sensitivity of the ET beta receptor and will be determined to monitoring mRNA expression. We also anticipate that the GTP to (GTP + GDP) binding ratio will be less in the aged animals suggesting increased G-protein activity and we will attempt to link ET-1 as a possible mediator. Understanding the mechanisms responsible for the decrease in RBF and GFR will aid in the development of novel treatments and methods for reversing or slowing the renal vascular changes that occur with age. These results may then improve the quality of life with age.