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.
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.
| Wang, Longfei; Fu, Tian-Min; Zhou, Yiming et al. (2018) Structures and gating mechanism of human TRPM2. Science 362: |
| Zhou, Yiming; Castonguay, Philip; Sidhom, Eriene-Heidi et al. (2017) A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358:1332-1336 |
| Gipson, Deb (2016) Clinical Trials in FSGS: Past Challenges and New Trial Designs. Semin Nephrol 36:453-459 |
| Greka, Anna (2016) Human genetics of nephrotic syndrome and the quest for precision medicine. Curr Opin Nephrol Hypertens 25:138-43 |
| Mundel, Peter; Greka, Anna (2015) Developing therapeutic 'arrows' with the precision of William Tell: the time has come for targeted therapies in kidney disease. Curr Opin Nephrol Hypertens 24:388-92 |
