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New Haven, CT 06520
United States of America
The dysfunction of the kidney filtration barrier results in nephrotic syndrome, a severe glomerular disease that manifests with massive protein loss in the urine. Our laboratory focuses on the filter lining cells, the podocytes, which are defective in almost all forms of proteinuric kidney diseases.
One laboratory has opened a new area of podocyte investigation by examining the relevance of endocytosis in podocyte biology. We identified that the functional consequences of loss of neuronal synaptic proteins, such as dynamin, synaptojanin 1, and endophilin extend beyond the synapse. Podocyte specific loss of these genes in mice results in severe proteinuria. These synaptic proteins are critical for recycling modified tight junction proteins such as nephrin in order to cope with the stress of daily plasma filtration.
We have also identified the importance of the podocyte cell-matrix by studying focal adhesion proteins that link integrins to the actin cytoskeleton. Inability of podocytes to adhere results in the loss of podocytes, resulting in neighboring podocytes undergoing effacement, where the cells collapse losing cell-cell junction proteins. By integrating genetic mice models of disease, we have identified the importance cell matrix proteins, talin, vinculin, and focal adhesion kinase are critical in maintaining the integrity of this filtration barrier.
Lastly, by utilizing proteinuric animal models, we have great interest in identifying therapeutic targets. Using RNA profiling of podocytes and glomeruli in the proteinuric mice, we have determined that podocyte associated activation of histone deacetylases may be detrimental in inducing the progression of chronic kidney disease. Use of FDA approved HDAC inhibitor, valproic acid, mitigated progression of CKD in mice proteinuric models. Salutary effects in a cohort of patients with proteinuria who had been on valproic acid was observed highlighting the potential therapeutic implications in slowing down the progression of chronic kidney disease.
Yale School of Medicine (Primary)
Harriet Margot Kluger, MD is the representative at this institution.