Role of Calpain in Podocyte Injury

Yale University, New Haven CT

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Abstract

? DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) often leads to irreversible deterioration of renal function that progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health problem and data obtained from the USRDS reveals that the number of new cases of ESKD in the United States is projected exceed 700,00 patients by 2015. As glomerular diseases secondary to podocyte dysfunction contribute up to 90% of all ESKD, a detailed molecular and genetic approach to identify mechanisms for podocyte development and repair may give us new insights for developing therapeutic agents and targets. Recent evidence suggests that cell matrix interactions are critical during podocyte health and disease, and are regulated by proteases, such as calpain. To further determine the importance, we have also identified that podocyte calapin activity induces endoplasmic reticulum stress (ER stress), an adaptive process put in place to protect cells from pathologic stimuli. In our preliminary data, we demonstrate marked talin1 proteolysis and activation of ER stress following podocyte injury, which are both attenuated with pharmacological inhibition of calpain. In Aim 1, we will define and further characterize the importance of podocyte specific calpain activity in modulating cell matrix regulation. In Aim 2, we will examine the mechanisms of calpain activation leading to ER stress and how it contributes to podocyte dysfunction. By completing these aims, we will have an opportunity to further expand our knowledge of calpain regulation and its downstream effects in podocyte homeostasis.