Nephrotic syndrome (NS) is characterized by heavy proteinuria and increased risk of loss of kidney function. It causes serious morbidity and high mortality, accounting for 15% of prevalent end-stage renal disease at an annual cost of more than $3 billion in the US. There is no effective treatment for most cases of NS caused by genetic mutations. Our research has been focused on a monogenic form of NS caused by a missense mutation (C321R) of LAMB2, one of the most commonly mutated genes in NS. Laminin 2 encoded by LAMB2 is a component of laminin-521 ( 5 2 1), the major laminin trimer of the glomerular basement membrane (GBM). Using our established knockout/transgenic mouse model, we have found that podocyte endoplasmic reticulum (ER) stress and subsequent defective secretion of misfolded C321R-LAMB2 from podocytes to the GBM lead to proteinuria. Furthermore, we have recently discovered an ER soluble factor that promotes the survival of ER-stressed podocytes. The overall goals of this proposal are to delineate molecular mechanisms regulating important death and survival pathways activated by the C321R-LAMB2 mutation-induced podocyte ER stress, to determine the contribution of podocyte ER stress in NS patients carrying putative deleterious missense variants, and to investigate novel treatment strategies for genetic forms of NS. To accomplish our research goals, we will utilize mouse genetic models and access two major human NS cohorts, Nephrotic Syndrome Study Network (NEPTUNE) and the Washington University Kidney Translational Research Core (WU KTRC). We have assembled an interdisciplinary team including multiple co-investigators and collaborators with the required expertise in pioneering ER stress research, human and mouse genetics, next generation sequencing, and high throughput screening. The proposed study will help us classify NS patients based on underlying molecular mechanisms, stratify disease risk, and discover highly-targeted treatments for NS patients caused by podocyte ER dysfunction.

Public Health Relevance

Nephrotic syndrome (NS) is an important kidney disease that causes proteinuria and progressive renal failure, and there is no effective treatment for genetic forms of NS. The goal of our research is to investigate podocyte ER stress as an important molecular mechanism linking genetic variation to disease phenotype in NS and to develop novel therapeutics for NS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105056-04
Application #
9930584
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Sadusky, Anna Burkart
Project Start
2017-08-15
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130