Albuminuria is the single strongest predictor of kidney function decline and is associated with the presence and severity of cardiovascular disease and predicts mortality. Dysfunction of podocytes is the major culprit of glomerular disease causing albuminuria. The demonstrated role of podocyte TRPC5 signaling in the onset of albuminuria suggests therapeutic benefit in progressive glomerular diseases such as Focal Segmental Glomerulosclerosis (FSGS), a histopathological diagnosis with different pathogeneses including genetic mutations, drugs, viral infections, and most importantly, as the result of metabolic disease, such as diabetes, obesity and hypertension. As it stands, FSGS remains a devastating and largely untreatable disease associated with increased morbidity. We have previously demonstrated that a novel TRPC4/5 antagonist, ML204, is able to protect the kidney filter. However, highly potent and selective antagonists of TRPC5 have not been identified yet. In this proposal, we will improve and optimize our initial lead compound, ML204, and test its ability to reduce proteinuria in rodent models of disease. In order to develop these first-in-class compounds, we will utilize an iterative medicinal chemistry approach and integrated DMPK studies which will allow us to evaluate not only potency and selectivity;but also the in vitro and in vivo DMPK properties of newly made compounds in a timely manner. These selective TRPC5 antagonists not only offer a unique opportunity to test the hypothesis in this proposal, but also, to help advance the field towards a drug development.

Public Health Relevance

Kidney filtration is an important process in retention of vital proteins in the blood and removing waste from the body and damage to this filtration can lead to albuminuria (albumin present in the urine), the single strongest predictor of kidney function decline. It has been shown that the ion channel TRPC5 mediates filtration barrier injury. This work could have substantial contributions to medicine due to the fact that Focal Segmental Glomerulosclerosis is a largely untreated disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01DK103658-01
Application #
8800654
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Moxey-Mims, Marva M
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212