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.

Public Health Relevance

Kidney injury that damages the filtration barrier often presents with urinary protein loss. Often, this injury progresses to where patients require dialysis and kidney transplantation. Understanding the biology is of paramount importance as more than 20 million people in the United States have chronic kidney disease. In this grant proposal, we plan to clarify the mechanism that results in the loss of integrity of the filtration barrier, so that nvel therapeutic options are available in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083294-07
Application #
9058519
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2009-04-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Lausecker, Franziska; Tian, Xuefei; Inoue, Kazunori et al. (2018) Vinculin is required to maintain glomerular barrier integrity. Kidney Int 93:643-655
Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438
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Inoue, Kazunori; Balkin, Daniel M; Liu, Lijuan et al. (2017) Kidney Tubular Ablation of Ocrl/Inpp5b Phenocopies Lowe Syndrome Tubulopathy. J Am Soc Nephrol 28:1399-1407
Zhou, Han; Tian, Xuefei; Tufro, Alda et al. (2017) Loss of the podocyte glucocorticoid receptor exacerbates proteinuria after injury. Sci Rep 7:9833
Tian, Xuefei; Ishibe, Shuta (2016) Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease. Nephrol Dial Transplant 31:1577-83
Hassan, Hossam; Tian, Xuefei; Inoue, Kazunori et al. (2016) Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes. J Am Soc Nephrol 27:1055-65
Inoue, Kazunori; Ishibe, Shuta (2015) Podocyte endocytosis in the regulation of the glomerular filtration barrier. Am J Physiol Renal Physiol 309:F398-405
Tian, Xuefei; Kim, Jin Ju; Monkley, Susan M et al. (2014) Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest 124:1098-113
Soda, Keita; Ishibe, Shuta (2013) The function of endocytosis in podocytes. Curr Opin Nephrol Hypertens 22:432-8

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