Effects of Diet and Disease on Renal Oxylipins and Related Enzymes in the Han:SPRD-Cy rat Model of Cystic Kidney Disease

Abstract

Selective inhibition of cyclooxygenase (COX) derived oxylipins reduces disease progression in the Han:SPRD-Cy rat model of cystic kidney disease, but the roles of lipoxygenase (LOX) and cytochrome P450 (CYP) derived products in this disease are not known. Dietary soy protein (SP), fish oil (FO) and flax oil (FXO) are beneficial in retarding renal disease progression in this and other models of cystic kidney disease and can alter renal oxylipin production through different mechanisms. The general objectives of this thesis were to: 1) investigate the effects of disease on renal oxylipin levels (produced from the three enzymatic pathways); 2) investigate the synergistic and additive effects of combining dietary SP with FO or FXO on disease progression, renal fatty acid composition, and renal oxylipin levels; 3) compare the effects of COX and LOX inhibitors on oxylipin levels and disease progression, in the Han:SPRD-Cy rat model of cystic kidney disease. Our research demonstrates that COX oxylipins are elevated and n-6 derived LOX metabolites are reduced in diseased kidneys in this model of cystic kidney disease. N-3 polyunsaturated fatty acid (PUFA) derived LOX oxylipins, including those derived from alpha-linolenic acid (ALA) and docosahexaenoic acid (DHA) were also lower in diseased kidneys, as were CYP derived oxylipins. The beneficial effect of SP on disease was associated with amelioration of several oxylipin alterations in parallel with a reduction in kidney disease progression, improvement in kidney function and blood pressure. However, adding dietary FO or FXO to the SP diet improved some but worsened other oxylipin alterations and did not provide further disease protection. Since both COX1 and COX2 activities are elevated in diseased kidneys, the effect of aspirin was examined; this treatment slowed disease progression and the decline in kidney function. On the other hand, inhibiting the LOX pathway had no effects on disease. Thus interventions that specifically inhibit COX while maintaining LOX and CYP may be more effective than general oxylipin inhibitors in slowing disease in this renal disorder.