Identifying New Molecular Pathways and Therapeutic Targets in Diabetic Kidney Disease
Lead Research Organisation:
University of Bristol
Department Name: Bristol Medical School
Abstract
Diabetic kidney disease (DKD) is the leading cause of kidney failure in the world and increasing at alarming rates due to the diabetes-inducing lifestyles we live. Currently the treatments for DKD are inadequate and many patients develop kidney failure needing dialysis or a kidney transplant. If this happens these patients are more likely to suffer from cardiovascular problems such as heart attacks and stroke and are much more likely to die prematurely.
Work by our laboratory has shown that a cell in the filtering unit of the kidney called the podocyte is important in the development of DKD and that the major hormone in diabetes, insulin, is able to beneficially signal to this cell. When podocyte-insulin signalling is lost it is detrimental to kidney function and kidney disease develops. We have developed a drug screening assay to identify new therapies that make the podocyte more insulin-sensitive and this project has identified a cell target we would like to follow up. We intend studying this target in mouse models of DKD and human podocyte cells in dishes to clarify if it might be a good treatment for patients with diabetic kidney disease in the future.
Work by our laboratory has shown that a cell in the filtering unit of the kidney called the podocyte is important in the development of DKD and that the major hormone in diabetes, insulin, is able to beneficially signal to this cell. When podocyte-insulin signalling is lost it is detrimental to kidney function and kidney disease develops. We have developed a drug screening assay to identify new therapies that make the podocyte more insulin-sensitive and this project has identified a cell target we would like to follow up. We intend studying this target in mouse models of DKD and human podocyte cells in dishes to clarify if it might be a good treatment for patients with diabetic kidney disease in the future.
Technical Summary
DKD is the leading cause of kidney failure in the world. Its natural history is dominated by progressive albuminuria in the majority of patients suggesting that the glomerular podocyte may be an early target cell in diabetes. Our group has shown that podocyte insulin resistance could be an early initiator of DKD. We have therefore developed a medium-high-throughput human podocyte insulin signalling assay and screened 1280 compounds using it. The "top hit" from this assay was a drug called Yoda1 which activates a mechanosensitive cell membrane stretch channel called piezo1. We therefore intend studying this channel in much greater detail using an in vivo diabetic mouse and in vitro human podocyte cell approach. We hypothesize that piezo1 activity is an important link between podocyte stretching (as occurs with an increased glomerular filtration load after a meal) and podocyte insulin responses. We also think activating it could be beneficial in treating DKD.
To address this hypothesis we have 3 aims to:
1. Assess if pharmacologically activating piezo1 with yoda1 in a mouse model of DKD is beneficial.
2. Genetically target and modify piezo1 activity specifically in the podocyte in diabetic and non-diabetic mice to assess the consequences of losing or hyper-stimulating its activity.
3. Define how piezo1 activity is controlled in the human podocyte and the molecular consequences for this cell of activating it.
Ultimately we hope this project will advance our understanding of the physiology of the podocyte and also identify a new therapeutic target to treat DKD.
To address this hypothesis we have 3 aims to:
1. Assess if pharmacologically activating piezo1 with yoda1 in a mouse model of DKD is beneficial.
2. Genetically target and modify piezo1 activity specifically in the podocyte in diabetic and non-diabetic mice to assess the consequences of losing or hyper-stimulating its activity.
3. Define how piezo1 activity is controlled in the human podocyte and the molecular consequences for this cell of activating it.
Ultimately we hope this project will advance our understanding of the physiology of the podocyte and also identify a new therapeutic target to treat DKD.