ER stress in glomerular disease: defining mechanisms and identification of new diagnostic and therapeutic targets
Co-Applicant(s): Ahsan Alam, Constantinos DELTAS, Joseph Bonventre, Louis-Philippe Laurin, Stéphane Laporte
Lay Abstract
Glomerular podocytes are vital in maintaining the structure and function of the glomerulus, the filtering unit of the kidney. Intact function of the endoplasmic reticulum (ER) is important for protein homeostasis in the podocyte, including production of components of the slit diaphragm, adhesion complexes and glomerular basement membrane (GBM). Disorders of ER function can contribute to disease. Diseases of the renal glomerulus, especially those initiated by immunological processes ("glomerulonephritis"), account for approximately half of the causes of chronic kidney disease in Canada. Treatment of patients with kidney disease with dialysis and kidney transplantation has resulted in a dramatic improvement in the survival of patients, but at a large cost to the Canadian economy. Fundamental research into the disordered mechanisms that lead to glomerulonephritis is essential to the understanding of these diseases, an understanding that will ultimately lead to therapy and prevention. In this proposal, we will study abnormalities in cellular pathways in the glomerulus involving the ER, and establish how ER function allows podocytes to maintain glomerular function in the normal kidney and in glomerular diseases. We will establish urinary biomarkers of ER diseases. The proposed studies will use a tissue-culture system, animal models of glomerulonephritis and human biosamples to characterize abnormalities contributing to the cause of the disease. The elucidation of basic mechanisms of the causes of disease, and testing of therapies in preclinical (animal) models is likely to be the most productive approach to the development of treatment strategies to human glomerulonephritis. The results of the proposed studies will eventually lead to improved strategies for therapies of kidney disorders.
