THE ROLE OF LACTOSYLCERAMIDE IN RENAL AGING AND DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Renal function declines with aging, leading to numerous medical complications. There is also an elevated prevalence of renal disease. As the elderly population is expanding, it is our goal is to identify factors that mediate kidney aging for the development of novel therapeutics to improve renal function in the aged and treat aged-related kidney disease. In vitro tissue culture studies suggest that glycosphingolipids regulate cellular processes such as inflammation and cell proliferation that are known to play roles in kidney aging and disease. However, it is not known if glycosphingolipids play an in vivo role in kidney aging in mammals. We have exciting preliminary data indicating that particular species of glycosphingolipids are elevated more than 8-fold in the kidney during aging. Moreover, caloric restriction (CR), the only known intervention that extends the mean and maximum lifespan in mammals as well as preserves kidney function during aging, completely prevents the observed elevation in glycosphingolipids in the aged kidney. Taken together, these data have led us to propose the following hypothesis: altered renal sphingolipid metabolism during aging leads to accumulation in glycosphingolipids which in turn mediate, at least in part, the decline in kidney function; CR prevents the accumulation of renal glycosphingolipids during aging, thus attenuating the decline in kidney function. This hypothesis will be tested with two specific aims: (1) determine the mechanism, location, and role for elevated renal glycosphingolipids during aging and (2) determine the mechanism by which CR prevents the elevation in renal glycosphingolipids during aging. At the completion of the studies included in this proposal, we will have established glycosphingolipids as key regulators of renal aging and identified novel targets for the development of CR mimetics to preserve kidney function in the elderly.