Glomerular Disease

The glomerulus has a critical function as the filtration barrier in the kidney. Podocytes, basement membrane, and endothelial cells function together to ensure the selective removal of metabolic waste products while retaining critical components of the circulation. Damage to this filtration barrier, often resulting in proteinuria, comprises the spectrum of glomerular diseases that account for approximately 80% of end-stage kidney disease. The Ishibe and Menon labs investigate pathways that are important to maintain the integrity of the kidney filtration barrier.

Dr. Ishibe’s lab has identified the critical role of clathrin coated endocytic processes and cell matrix regulation in the development and maintenance of podocytes, the epithelial cells lining the filtration barrier. They have generated in-vivo animal models with genetic knockout of genes implicated for endocytosis (dynamin, synaptojanin1, endophilin) and cell matrix (focal adhesion kinase, talin1, vinculin) regulation specifically in the podocytes. Leveraging these knockout mice that develop severe proteinuria and kidney failure, has also allowed the lab to identify potential targets for therapeutic interventions—e.g., inhibition of histone deacetylase and of calpain—that may have human applicability to mitigate the progression of glomerular diseases.

Dr. Menon’s lab showed that Shroom3 knockdown in podocytes inhibited Fyn activation, caused albuminuria and foot process effacement mimicking human minimal change disease (MCD). They identified enhanced AMP-Kinase signaling as the underlying mechanism. AMP-Kinase activation regulated podometrics, maintained podocyte survival and attenuated glomerulosclerosis (FSGS) when glomeruli are faced with hypertrophic stress, effectively switching FSGS to an MCD-like phenotype in the context of foot process effacement. The lab is using several murine models based on tissue-specific gene expression potential, glomerular injury and approved or novel pharmacologic agents to examine the switch of MCD to FSGS phenotype with the goal of identifying potential new glomerular therapeutics. Human applicability will be tested using approved studies from the NEPTUNE consortium - the largest nephrotic syndrome cohort.