The etiology of
diabetic nephropathy in
type 2 diabetes is multifactorial. Sustained
hyperglycemia is a major contributor, but additional contributions come from the
hypertension,
obesity, and
hyperlipidemia that are also commonly present in patients with
type 2 diabetes and nephropathy. The
leptin deficient BTBR ob/ob mouse is a model of type 2
diabetic nephropathy in which
hyperglycemia,
obesity, and
hyperlipidemia, but not
hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with
leptin replacement can reverse the morphologic and functional manifestations of
diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the
hypertriglyceridemia, using an
antisense oligonucleotide directed against
ApoC-III, an
apolipoprotein that regulates the interactions of VLDL (
very low density lipoproteins) with the
LDL receptor, is sufficient to ameliorate the nephropathy of
Type 2 diabetes. Antisense treatment resulted in reduction of circulating
ApoC-III protein levels and resulted in substantial lowering of
triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate
proteinuria or pathologic manifestations of
diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of
diabetic nephropathy are unlikely to be reduced by
lipid-lowering
therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other
therapeutics commonly employed in the treatment of diabetes and its complications.