Nephrotic syndrome is a major cause of kidney failure, and patients with this condition develop large amounts of proteinuria and elevated levels of plasma lipids (triglycerides and cholesterol). The immediate goal of the PI / applicant is to study in detail the mechanisms behind the development of hypertriglyceridemia in nephrotic syndrome. The PI's long term goal is to develop specific mechanism-based therapy for hyperlipidemia in nephrotic syndrome. The career development plan has been developed by the applicant, the primary mentor, and the two co-mentors to provide new and enhanced training in lipid biology, proteomic techniques, cell signaling, communication and presentation skills, grant and manuscript writing, and responsible conduct of research. There is a progressive increase in independence and greater involvement of the co-mentors in the later years of the grant. Timelines for each Specific Aim, allocation of independent laboratory space, periodic meetings of the applicant with the mentoring committee, expectations from the applicant and the specific role of each mentor are addressed in detail in the career development plan. In addition, the applicant is expected to write smaller foundation grants in the earlier years, and a R01 application in the last two years of the K Award. Research work currently being conducted by the PI has revealed an important role of Angiopoietin-like-4 (Angptl4) in the development of nephrotic syndrome in primary glomerular diseases like minimal change disease. Angptl4 is a secreted glycoprotein that is a known inhibitor of lipoprotein lipase and increased plasma levels of this protein result in the development of hypertriglyceridemia (a component of hyperlipidemia). Studies conducted by the PI reveal that increased secretion of this protein from the podocyte results in the development of proteinuria (Clement LC Nature Medicine 2011). In this proposal, the applicant will study the regulation of Angptl4 gene expression in the podocyte by glucocorticoids, and investigate the development of hypertriglyceridemia resulting from podocyte secretion of Angptl4 into the circulation in nephrotic syndrome. Hypothesis: The upregulation of podocyte Angptl4 expression in minimal change disease is reduced by treatment with glucocorticoids, and is mediated via binding of the glucocorticoid receptor to a negative glucocorticoid response element in the Angptl4 promoter. In primary glomerular disease, the sialylation of podocyte secreted Angptl4 influences its ability to leak into the circulation, inhibt lipoprotein lipase activity, and produce hypertriglyceridemia. Circulating Angptl4 is transported on the surface of HDL and inhibits endothelium bound lipoprotein lipase directly, and via its interaction with apolipoproteins C-II and C-III.
In Specific Aim 1, the regulation of the Angptl4 promoter activity by glucocorticoids will be studied.
In Specific Aim 2, the influence of sialylatin and other forms of posttranslational modification in the leakage of podocyte secreted Angptl4 into the circulation and the resulting development of hypertriglyceridemia will be investigated.
In Specific Aim 3, putative interactions of Angptl4 with apolipoproteins C-II (activator of lipoprotei lipase) and C-III, (inhibitor of lipoprotein lipase) on the surface of HDL will be studied.
|Chugh, Sumant S; Macé, Camille; Clement, Lionel C et al. (2014) Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease. Front Pharmacol 5:23|
|Clement, Lionel C; Mace, Camille; Avila-Casado, Carmen et al. (2014) Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med 20:37-46|