Abstract 18509: Defining Renal Uptake of Circulating Lipids

Abstract

A prominent histological feature of chronic kidney disease, including that due to diabetes, is the accumulation of neutral lipids in the nephron. However, existing research on kidney lipid metabolism is limited. Therefore we characterized lipid accumulation in mouse models. We hypothesized that the major source of lipids in the kidney is circulating triglyceride (TG)-rich lipoproteins brought into the cells of the kidney via the coordinated action of lipoprotein lipase (LPL) and cluster of differentiation 36 (CD36). To test this hypothesis, we fasted mice overnight and inhibited LPL and CD36. We did not observe a change in TG accumulation in the kidney when LPL action was blocked using with poloxmer 407. We then used a microsomal TG transfer protein inhibitor, which inhibits TG-rich lipoprotein assembly, to lower circulating TG-rich lipoproteins. Intracellular kidney TG did not decrease but in fact increased up to 40% in the fasted state after the inhibitor was given, mirroring what was seen in the liver. There was no difference in TG accumulation in the kidneys of fasted Cd36 -/- mice. Furthermore, we did not observe a change in uptake of radiolabeled oleic acid in the kidneys of these mice. Genes which regulate fatty acid oxidation or de novo lipogenesis were also unchanged in Cd36 -/- compared to Cd36 +/+ . Surprisingly, apoC-III deficiency increased renal uptake of a TG-emulsion, as had been found in the liver. Finally, we measured TG in kidneys from streptozotocin-treated and Akita diabetic mice without renal failure. Neither of these models accumulated higher amounts of TG compared to non-diabetic controls; however, Akita mice down regulated fatty acid oxidation genes and had twice the intracellular free fatty acids. These findings provide novel insight into the lipid biochemistry of the kidney, showing it differs from other high energy requiring peripheral organs such as heart.