Glomerulosclerosis is the common pathologic process responsible for 90% of End Stage Kidney Disease (ESKD) associated with diabetes, hypertension, IgA nephropathy, Focal Segmental Glomerulosclerosis (FSGS), lupus and other glomerular diseases. Together these diseases cost approximately $18 billion per year in the US, and carry high morbidity and mortality. They are increasing in prevalence and are commoner in minority populations. They affect both children and adults, although ESKD is particularly a disease of aging with average onset of ESKD treatment at 64 years. The central hypothesis underlying this work is that glomerulosclerosis is caused by depletion of one of the glomerular cell types, the podocyte. During the prior grant cycle we developed a new transgenic model system in the rat where we can deplete podocytes by an amount and at a time of prior choosing. We show that podocyte depletion does indeed cause all the features of FSGS in a dose-dependant manner. Second we have developed a new method for counting podocytes in glomeruli. Third, we have shown how glomerular enlargement during aging on a high calorie diet causes relative podocyte depletion that predisposes to glomerulosclerosis, and how this can be prevented by calorie restiction. Because we know that hypertension is commonly associated with glomerulosclerosis and progression of glomerulosclerosis to ESKD, these new tools and concepts will be used to test specific hypotheses relevant to human glomerulosclerosis:
Aim 1 : Podocyte depletion itself causes systemic hypertension and mesangial expansion, an important pathologic component of early glomerulosclerosis in man.
Aim 2 : Test the hypothesis that limitation of the ability of the podocyte to increase in size makes the glomerulus more susceptible to glomerulosclerosis, while enhancement of podocyte's ability to increase in size prevents glomerulosclerosis, by using transgenes of the mTOR pathway of cell size control to modulate podocyte size.
Aim 3 : Validate the novel concepts of podocyte alteration in phenotype in response to stress that we have termed """"""""adaptation"""""""" and """"""""decompensation"""""""" in two rat models of glomerulosclerosis, with the underlying concept that understanding the biology of this process will allow us to develop markers for human podocyte stress as well as new approaches to treat and prevent podocyte stress before it results in loss of podocytes and consequent glomerulosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046073-16
Application #
7763948
Study Section
Special Emphasis Panel (ZRG1-RUS-E (02))
Program Officer
Flessner, Michael Francis
Project Start
1993-08-01
Project End
2011-07-31
Budget Start
2010-02-01
Budget End
2011-07-31
Support Year
16
Fiscal Year
2010
Total Cost
$289,903
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
Ding, Fangrui; Wickman, Larysa; Wang, Su Q et al. (2017) Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome. Kidney Int 92:1515-1525
Fukuda, Akihiro; Minakawa, Akihiro; Sato, Yuji et al. (2017) Urinary podocyte and TGF-?1 mRNA as markers for disease activity and progression in anti-glomerular basement membrane nephritis. Nephrol Dial Transplant 32:1818-1830
Madill-Thomsen, K S; Wiggins, R C; Eskandary, F et al. (2017) The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla. Am J Transplant 17:2117-2128
Hato, Takashi; Winfree, Seth; Day, Richard et al. (2017) Two-Photon Intravital Fluorescence Lifetime Imaging of the Kidney Reveals Cell-Type Specific Metabolic Signatures. J Am Soc Nephrol 28:2420-2430
Nishizono, Ryuzoh; Kikuchi, Masao; Wang, Su Q et al. (2017) FSGS as an Adaptive Response to Growth-Induced Podocyte Stress. J Am Soc Nephrol 28:2931-2945
Naik, Abhijit S; Afshinnia, Farsad; Cibrik, Diane et al. (2016) Quantitative podocyte parameters predict human native kidney and allograft half-lives. JCI Insight 1:
Wagner, Mark C; Campos-Bilderback, Silvia B; Chowdhury, Mahboob et al. (2016) Proximal Tubules Have the Capacity to Regulate Uptake of Albumin. J Am Soc Nephrol 27:482-94
Hodgin, Jeffrey B; Bitzer, Markus; Wickman, Larysa et al. (2015) Glomerular Aging and Focal Global Glomerulosclerosis: A Podometric Perspective. J Am Soc Nephrol 26:3162-78
Fukuda, Akihiro; Sato, Yuji; Iwakiri, Takashi et al. (2015) Urine podocyte mRNAs mark disease activity in IgA nephropathy. Nephrol Dial Transplant 30:1140-50
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

Showing the most recent 10 out of 26 publications