Plasminogen in glomerular disease progression

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Linked publications & trials

Abstract

Project Summary Despite significant evidence identifying the podocyte as the key glomerular cell target for injury, validated therapeutic targets are scarce and commercially available cell-specific therapy is lacking. Additionally, given the heterogeneous nature of proteinuric kidney disease, biomarkers to identify patients at high versus low risk for progression to end-stage kidney disease (ESKD) are needed. Our long-term goal is to identify key regulatory pathways and therapeutic targets in the treatment of proteinuric kidney disease. We previously identified the serine protease plasminogen as a mediator of direct podocyte injury and a potential targetable urinary biomarker that correlates with albuminuria, edema and renal function. Recently, we developed a de novo electro- chemiluminescent immunoassay (ECLIA) to accurately measure urinary plasminogen and demonstrated its utility in predicting ESKD progression in a large, diverse patient cohort. The overall objective of this application is to define the role of plasminogen as a mediator of podocyte injury and a potential therapeutic target in progressive glomerular disease. Our hypothesis is that under normal conditions with an intact glomerular filtration barrier, podocytes are not exposed to plasminogen. In proteinuric disease, plasminogen induces podocyte injury, with plasminogenuria serving as a targetable biomarker. Amiloride (and 6-substituted hexamethylene amiloride) derivatives could have podocyte protective properties by inhibiting urokinase plasminogen activator (uPA), the serine protease that specifically cleaves the proenzyme/zymogen plasminogen to form the active plasmin. Our hypothesis will be tested by pursuing two specific aims: Aim 1 will define the role of plasminogen in podocyte injury and glomerular disease. We will develop a podocyte-specific plasminogen-targeted network controlling podocyte focal adhesion dynamics, define the in vivo molecular mechanisms linking plasminogenuria to podocyte injury, and test the molecular interaction between plasminogen and LIM-nebulette in regulating podocyte structural integrity. In Aim 2, we will define plasminogen as a targetable biomarker in proteinuric kidney disease. We will define the association between baseline urinary plasminogen and longitudinal outcomes in a general CKD cohort as well as patients with glomerular disease. We will use rational design and medicinal chemistry to optimize plasminogen inhibitors for podocyte protection. Additionally, we will also test the efficacy of novel plasminogen inhibitors in experimental glomerular disease. The work proposed is expected to characterize the role of plasminogen in podocyte injury and glomerular disease progression. If successful, the results could define plasminogen as a targetable biomarker in the treatment of proteinuric kidney disease.