Chronic kidney disease (CKD) often leads to irreversible deterioration of kidney function that often progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health issue and data obtained from the USRDS reveals that the number 20 million patients in the United States suffer from CKD. As glomerular diseases secondary to podocyte dysfunction account for greater than 80% of all CKD, an intensive molecular and genetic approach to identify mechanisms for podocyte development, maintenance and repair may provide new therapeutic targets Recent evidence suggests an important role of clathrin mediated endocytosis orchestrating podocyte function. Using genetic mouse models, we have discovered proteins involved in mediating clathrin mediated endocytosis such as synaptojanin 1, dynamin, and endophilin, are indispensible for maintaining a normally functioning filtration barrier. We have further extended our findings that GAK, a protein important for uncoating clathrin, is equally important. To probe the mechanism, a microarray analysis on enriched glomeruli was performed revealing a plethora of actin-regulated genes containing a serum response element regulated by the serum response factor. We have also taken advantage of human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS), which also demonstrated reduced GAK expression and increased serum response factor expression. Therefore In Aim 1, we will define the fundamental mechanisms on how loss of GAK contributes to podocyte dysfunction through abnormal actin dynamics mediated by serum response factor.
In Aim 2, we will characterize the role of GAK's C-terminus to stabilize podocyte function and further investigate the link between endocytosis and actin in podocytes. Our mouse models of disease with human FSGS biopsy findings provide impetus to further define the role of clathrin- mediated endocytosis in the formation and maintenance an intact glomerular filtration barrier.

Public Health Relevance

Damage to the kidney filtration barrier resulting in urinary protein loss accounts for approximately 80% of end stage kidney disease where nearly 600,000 patients in the United States require dialysis or kidney transplantation. Understanding the fundamental biology is a necessity as currently, there is a lack of therapeutic options. In this grant proposal, we plan to elucidate the underlying components required to maintain a normally functioning filtration barrier, so that novel treatments can be discovered in the near future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK093629-05A1
Application #
9382054
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-09-27
Project End
2022-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
5
Fiscal Year
2017
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
06520
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
Mathew, Sijo; Palamuttam, Riya J; Mernaugh, Glenda et al. (2017) Talin regulates integrin ?1-dependent and -independent cell functions in ureteric bud development. Development 144:4148-4158
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

Showing the most recent 10 out of 11 publications