Microsoft word - talernsak's proposal.doc

Effect of pioglitazone on inflammatory markers and renal outcome in naïve IgA nephropathy By Talerngsak Kanjanabuch, M.D., M.S. Effect of pioglitazone on inflammatory markers and renal outcome in naïve IgA
nephropathy.
Talerngsak Kanjanabuch, M.D., M.S.1, Wipawee Kithikovot, M.D.2, Somchai Eiam-Ong, M.D.1 Departments of Medicine1 and Pathology 2, Devision of Nephrology, Department of Medicine, INTRODUCTION
IgA nephropathy is the most common cause of glomerulonephritis in all around the world. It becomes a leading cause of end stage renal failure, which starves the patient’s pocket with high cost of renal replacement therapy. The nowadays treatments aim to slow the disease progression, for instance, steroid can only decrease severity of proteinuria and fish oil can only slow the rate of glomerular filtration rate (GFR) declination. No drug is able to cure the disease or even stop IgA nephropathy is characterized by diffuse mesangial deposition of IgA with mesangial proliferation and matrix expansion. The mechanisms of mesangial proliferation have been studied in detail in animal models, particularly anti-Thy 1.1 in the rat. These studies have shown the key role of cytokines and growth factors in mesangial proliferation, particularly platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), and in the subsequent matrix production and sclerosis, transforming growth factor-beta (TGF-β). Studies of renal biopsies in human IgA nephropathy also support the role of PDGF and TGF-β. As yet these pathogenic insights shed the light on a specific treatment to stop or reduce these cytokine production and anticipate the treatment to cure the disease. Effect of pioglitazone on inflammatory markers and renal outcome in naïve IgA nephropathy By Talerngsak Kanjanabuch, M.D., M.S. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a member of the nuclear hormone receptor superfamily, and a pharmacological target for the novel antidiabetic thiazolidinediones (TZDs). Similar to other members of this family (steroid hormone, thyroid hormone, etc.); PPAR-γ contains both ligand-binding and DNA-binding domains. PPAR-γ forms a heterodimeric complex with retinoic X receptor, translocates to the nucleus, and binds to defined PPAR response elements in the promotor regions of specific target genes. In this way, PPAR-γ ligands can regulate gene expression, either positively or negatively. PPAR-γ plays an important role in numerous cellular processes, both metabolic and non-metabolic effects. PPAR-γ can enhance insulin sensitivity, decrease hepatic glucose production and decrease LDL level, linked to amelioration of diabetic nephropathy in both human and animal models. PPAR-γ has a variable role in cell cycle regulation depending on the type of studied cell. PPAR-γ tends to inhibit cell growth and promotes differentiation, decrease inflammation, and inhibit ECM accumulation. Previously published in vivo data has shown that TZD ameliorated development of glomerulosclerosis and tubular fibrosis in both diabetic rat model and the hypertensive non- diabetic 5/6-nephrectomy rat model. We hypothesize that the PPAR-γ agonist, pioglitazone, could slow IgA nephropathy disease progression by ameliorating cytokine production. SPECIFIC AIMS
1. Examine the role of pioglitazone in delay disease progression. 2. Determine the role of PDGF, bFGF, and TGF-β before and after pioglitazone treatment by measuring urine mRNA and protein expression. 3. Determine the factors relating to disease response.

Source: http://www.arckfas.chula.ac.th/Talernsak's%20Abstract.pdf