MECHANISMS OF ALTERED PHOSPHATE HOMEOSTASIS IN THE AGED

Georgetown University, Washington DC

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Abstract

There is growing concern over the effects of aging on tissue metabolism and bone density. Indeed, in addition to bone loss, the reduction of intracellular high energy phosphates can lead to decreased tissue metabolism, and can have severe consequences in brain, cardiac and renal tissues. Thus, determining the mechanisms contributing to reduced Pi homeostasis in the aging animal is an important issue. The kidney is the primary regulator of Pi excretion, and regulation of renal Pi uptake is dependent on renal type II sodium-Pi (NaPi-2) transporters. Therefore, factors that affect NaPi-2 expression have dramatic effects on Pi handling, and intracellular Pi concentration. We have previously shown that there is a PTH-independent decline in renal Pi reabsorption with age (from weanling to 2 years of age), but the mechanisms responsible for this decline are unclear. In addition, we have recently found NaPi-2 expression in rat brain, and have determined that central NaPi-2 transporters are regulated by cerebrospinal fluid Pi concentration, and brain NaPi-2 transporters may play a role in regulating renal NaPi-2 expression. This supports the concept that there may be a central signal transduction mechanism for initiation of Pi homeostasis, mediated by central NaPi-2. Thus, central NaPi-2 may be acting as a "Pi sensor" and signal transduction mechanism to higher levels in the brain, as well as to the kidney, the primary regulator of plasma Pi levels. This proposed brain/kidney interaction to regulate Pi homeostasis is novel, and this pilot will assess NaPi-2 expression in brain and kidneys of aging rats, and begin to assess potential age-related defects in the regulatory mechanisms, which reduce Pi homeostasis in the aging animal, and contribute to bone and tissue degeneration. The innovative concepts addressed include, the regulation of central NaPi transporters, defects in the mechanisms controlling NaPi-2 expression with age, and the potential central control of Pi homeostasis through a NaPi-2-associated mechanism. The specific aims of this application are: to characterize the response of central NaPi-2 transporters to factors that regulate Pi handling; and to determine the role of growth hormone and dietary Pi on NaPi-2 transporters expression in the brain and kidney as the animal ages. This will provide valuable information regarding the importance of NaPi-2 in regulating central and peripheral Pi homeostasis, as well as factors that contribute to the age-related reduction in Pi transport.