News & Research

    University of Southern California, Los Angeles, California

Role of the succinate receptor GPR91 in diabetic nephropathy

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Complications\Neuropathy

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Research Description

Diabetes mellitus is the most common cause of kidney damage.  Renin, a hormone produced mainly by the kidneys is a key factor in the activation of a mechanism that is highly active in diabetes and increases blood pressure and can damage a number of organs including the kidneys.  Diabetes is featured by low renin but high prorenin (renin precursor) plasma concentrations which can also activate disease processes.  However, the source and the mechanism of prorenin activation is not fully understood.  Our recent work showed that increased glucose concentrations that are relevant to conditions at the onset of diabetes directly cause renin release through a metabolic receptor in the kidneys. Also, we believe that the inhibition of the newly identified prorenin receptor in one particular compartment of the kidney could protect the kidneys from diabetic damage. These newly identified receptors and their signaling mechanisms may interact and regulate prorenin synthesis in the kidneys. Our aim is to clarify the mechanistic details of these processes in diabetic kidney disease and based on the acquired new information help to develop new drugs and therapeutic approaches for the more effective treatment of diabetic complications in many organs including the kidney, heart as well as systemic hypertension.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

The focus of this research project is diabetic kidney disease, one of the most common and serious complications of diabetes. We aim to characterize the (patho)physiological role of succinate and GPR91, a novel metabolic signaling cascade within the kidney, and its role in diabetes pathology.  The broad, long-term objective of our work is to identify and validate novel therapeutic targets and diagnostic approaches for the more effective treatment and earlier diagnosis of diabetic kidney disease. These studies are also highly relevant to other organ complications of diabetes since there are organs other than the kidney in which this novel signaling mechanism (GPR91) is in place (heart, blood vessels, adipose tissue, retina, etc). Therefore, these studies will potentially result in high reward. This project applies a basic science approach which itself may provide paradigm-shifting result and a breakthrough in diabetes research. However, we have plans to translate these findings to humans in subsequent clinical translational studies. In addition to the design of new therapeutic strategies (GPR91 inhibitors), we aim to develop urinary succinate as a novel biomarker and predictor of diabetic kidney damage.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Our project will help understand how and what goes wrong within the kidney and possibly in other organs when blood sugar levels increase in early diabetes. We study one particular, newly discovered mechanism that seems to be playing an important role in the diabetic kidney and other organs. When this is successfully accomplished then we will prove that blocking this specific mechanism is a potentially new, effective therapeutic intervention to prevent diabetic kidney damage. Therefore, our work may result in the development of new drugs and clinical tests for the more effective treatment and earlier diagnosis of diabetic complications.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. In the United States alone, about a third of the 21 million Americans with diabetes go on to develop chronic kidney disease. Since the focus of my research laboratory is renal (patho)physiology and pathology, diabetic kidney disease has been one of our primary interests. Development of novel and better therapeutic and diagnostic strategies for diabetic patients will have a huge impact. This ADA award will provide strategically very important help in the early phase of our research when we validate a new therapeutic target in diabetes. The successful accomplishment of this research project will help me prepare for the next step to design and obtain major funding for a human clinical translational study.

In what direction do you see the future of diabetes research going?

Although molecular and genetic approaches are in the center of diabetes research, basic science and whole systems physiological approaches are absolutely necessary. I hope that preclinical testing and basic science diabetes research will continue to receive considerable funding and priority.