There is now strong evidence that FSGS is caused by podocyte depletion due to accelerated podocyte loss from glomeruli. We have shown that relative podocyte depletion can also occur if glomeruli enlarge without actually reducing the number of podocytes. Podocytes have limited capacity to divide and be replaced and therefore depend on hypertrophy to compensate for increased glomerular size during normal growth of childhood and especially in association with excessive glomerular growth such as occurs in association with obesity and diabetes. The hypothesis to be tested is that FSGS and progression to ESKD can be initiated and driven by failure of podocytes to respond adequately to hypertrophic stress during increased glomerular growth. To test this hypothesis we developed a new podocin-AA-4EBP1 transgenic rat model designed to specifically limit podocyte enlargement with the expectation (proven to be correct by preliminary data) that podocyte- specific expression of the transgene will predispose to development of FSGS during normal growth. We will use the model to test the hypothesis that growth itself can trigger the FSGS pathways to progression in susceptible individuals through the mTOR pathway. We will determine whether FSGS and progression in this model can be accelerated by factors that increase kidney growth such as uninephrectomy (as commonly occurs during transplant donation or nephrectomy for carcinoma of the kidney), or by insulin and growth factor treatments. We will determine whether FSGS and progression can be prevented by drugs in common use that will prevent glomerular growth such as calorie restriction, rapalogues and metformin. We will also test the hypothesis that angiotensin2 blockade will not prevent glomerular enlargement or the initial FSGS lesions, but will prevent accelerated glomerulosclerosis. If these hypotheses are correct then relatively simple steps, which are within current therapeutic capability, could significantly retard or prevent development of FSGS, glomerulosclerosis and progression to ESKD. The nation is facing an epidemic of overweight, obesity and type 2 diabetes (with parallel glomerular enlargement) affecting both adults and children with particular impact on minority groups. The focus of this application is therefore both timely and important as we strive to reduce the prevalence of ESKD currently costing >$50 billion annually with high mortality and morbidity for patients and their families.

Public Health Relevance

Progressive glomerular diseases such as FSGS particularly impact children and young adults who are undergoing rapid body growth, and are accelerated by overweight and obesity such as often occurs in association with diabetes. Both body growth and weight gain cause the filtering units in the kidney (the glomeruli) to enlarge so that the specialized cells whose job is to maintain the glomerular filtration barrier (the podocytes) become stressed and damaged resulting in the patchy scarring process called glomerulosclerosis. We have developed a novel transgenic rat model system to test the hypothesis that a mismatch between glomerular and podocyte growth can be an initiating factor causing accelerated glomerulosclerosis, and that relatively simple steps taken to prevent excessive glomerular growth by dietary and available drugs in current therapeutic use can prevent FSGS and progression to End Stage Kidney Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK046073-17A1
Application #
8236584
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
1993-08-01
Project End
2016-08-31
Budget Start
2011-09-20
Budget End
2012-08-31
Support Year
17
Fiscal Year
2011
Total Cost
$338,213
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Kikuchi, Masao; Wickman, Larysa; Hodgin, Jeffrey B et al. (2015) Podometrics as a Potential Clinical Tool for Glomerular Disease Management. Semin Nephrol 35:245-55
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