Treatment of Diabetic Nephropathy through Modulation of Lipoprotein Metabolism
Genetic and environmental factors contribute to the risk of diabetic nephropathy (DN) among people with diabetes. Inflammation is a key feature of DN. Inflammation is likewise a key feature of atherosclerosis. Hyperlipidemia plays a key causal role in atherosclerosis and its relationship to the inflammatory processes is quite well-studied. However, the role of hyperlipidemia in DN is less well explored. However, there is evidence linking hypertriglyceridemia with DN. A mechanism that links hyperlipidemia with atherosclerosis is the production of adducts between proteins and oxidized lipids. These adducts are epitopes that are recognized by the innate and adaptive immune responses and initiate an inflammatory process. We present evidence that oxidation epitopes present in human atherosclerosis are also present in DN. Thus, the premise of this proposal is that there is a common etiology between the inflammatory processes that underlie atherosclerosis and diabetic nephropathy. Ionis, Inc. has developed antisense oligonucleotides (ASOs) against apoC3, for the treatment of hypertriglyceridemia. Reducing apoC3 levels increases lipoprotein lipase-mediated removal of triglycerides from the bloodstream, primarily in adipose tissue. The anti-apoC3 ASOs are safe and effective, and currently in use in the clinic. The two principal investigators of this P&F proposal, Alan Attie and Charles Alpers, identified the BTBR-ob/ob mouse as an excellent model of human DN. The objective of this P&F project is to test the hypothesis that targeted ASO therapy for the dyslipidemia characteristic both of the BTBR-ob/ob mouse and humans with T2D will prevent the development of DN. The project will develop a treatment protocol using Ionis ASOs to normalize triglycerides in BTBR-ob/ob mice. Animals will then be treated and their nephropathy analyzed by measurement of urinary albumin, total protein, and urea. Kidneys will be analyzed histologically and by electron microscopy. The kidneys will be probed for the expression of lipid oxidation protein epitopes similar to those seen in atherosclerotic lesions. The studies will determine whether diversion of plasma lipids to adipose tissue will spare kidneys of nephropathy in the setting of type 2 diabetes.