Identify the Underlying Mechanisms Driving the Pathogenesis of Diabetic Nephropathy

My research focuses on understanding the cellular and molecular mechanisms of different types of kidney disease and to identify the signalling pathways that regulate kidney disease. Understanding the components in these signalling pathways and their mechanisms of action is key for developing therapeutic approaches that will improve kidney function. Diabetes is the leading cause of kidney failure. Kidney diseases are now the major cause of premature death worldwide. More than 500 million persons worldwide and approximately one in ten adults have some form of kidney damage. This devastating illness is a major health problem in the United States. Over 4 million Americans are affected by some form of kidney disease. The US Renal Data System estimates that by 2020, more than 700,000 Americans will have end stage renal disease, with more than 500,000 requiring dialysis and more than 250,000 receiving a transplant. The Medicare program spends approximately $24 billion per year for care of U.S. patients with end-stage kidney failure. National Institute of Health fact sheets shows including the cost to other payers and out-of-pocket expenses, the total annual bill for treating kidney failure is over $35 billion. So my area of research is extremely important to the national interest of United States of America.

After joining at Department of Medicine I took up a new challenge of investigating the molecular signalling mechanism of transforming growth factor beta (TGF-β) in chronic kidney disease (CKD). Gradual loss of kidney function is called chronic kidney disease (CKD) or chronic renal insufficiency. TGF-β is a member of a family of dimeric polypeptide growth factors. TGF-β exerts its various biological and immunological functions through complex signalling pathways. Increases or decreases in the production of TGF-β have been linked to numerous disease states, including atherosclerosis and fibrotic disease of the kidney, liver, and lung. I discovered a novel signalling mechanism how TGFβ play a role in CKD. I showed that TGFβ acts through two important enzymes, phosphatidylinositol 3–kinase (PI3K) and Act, which leads to expression of a gene called plasminogen activator inhibitor-1 (PAI- 1). PAI-1, a member of the SERPIN (for Serine Protease inhibitor) family, is the primary physiological inhibitor of plasminogen activators. It is a single-chain, 50-kDa glycoprotein. Under pathologic conditions elevated levels of PAI-1 is associated with renal fibrosis. Renal fibrosis is the final common manifestation of a wide variety of chronic kidney diseases (CKD). For the first time my data represented a novel mechanism of PAI-1 gene expression in response to TGFβ, which plays a pathologic role in kidney damage.

My study also investigated the pathophysiology of diabetic nephropathy. Diabetic nephropathy refers to the deleterious effect on kidney structure and/or function caused by diabetes mellitus. Clinically, diabetic nephropathy is characterized by a progressive increase in proteinuria and decline in GFR, hypertension and a high risk of cardiovascular morbidity and mortality. It is the most common single cause of end-stage renal disease (ESRD) in the United States. According to the Centres for Disease Control and Prevention (CDC), in 2011, about 25.8 million people in the U.S. has diabetes and more than 202,290 people with ESRD due to diabetes were either on chronic renal dialysis or had a kidney transplant. Both type 1 and type 2 diabetes can lead to diabetic nephropathy, although type 1 is more likely to lead to ESRD. The pathophysiologic mechanisms of diabetic nephropathy are incompletely understood. In 2008, I got an outstanding research achievement in the field of diabetes. I discovered a novel molecular pathway underlying diabetic nephropathy. I demonstrated that Rector, a novel binding partner of the signalling molecule mammalian target of rapamycin complex (motor), negatively regulates TORC1 activity to control basal protein synthesis, thus conferring tight control on cellular hypertrophy, which is one of the pathological features of diabetic nephropathy. This study provided a better understanding of the molecular mechanism involved in the diabetic kidney. This pathway may provide novel molecular targets for the design of rational therapies to prevent this disease. This innovative and important work was published in the prestigious journal, Cellular Signalling.

Journal of Nephrology and Urology is an Open Access peer-reviewed publication that discusses current research and advancements in diagnosis and management of kidney disorders as well as related epidemiology, pathophysiology and molecular genetics.

To submit a new manuscript authors should use the online submission system. Authors may submit their manuscript via online tracking system https://www.imedpub.com/submissions/nephrology-urology.html or as an attachment to email:  nephrolurol@imedpubjournals.com

Regards
Mercy Eleanor
Editorial Assistant
Journal of Nephrology and Urology