We will test the hypothesis that relative podocyte depletion in relation to glomerular area to be served causes glomeruloscierosis (GS). GS is the glomerular scarring process that is associated with progressive loss of renal function leading to ESRD in diabetic, hypertensive, Focal Segmental GS (FSGS) and in hereditary and immune forms of GS. Together these conditions account for about 90 percent of ESRD, major morbidity/mortality and a cost of more than 10 billion dollars per year in the US alone. ESRD is approaching epidemic proportions as the population ages. We know from autopsy reports that GS occurs with increasing frequency above 40 years of age. GS is well documented to be associated with podocyte injury. New data from experimental animals and diabetic man have reinforced the concept that it is the relationship between glomerular area and podocyte count that is critical. Each differentiated podocyte has limited capacity to divide and to cover an increased area of GBM. We hypothesize that if a threshold value for Glomerular Area Per Podocyte (GAPP) is exceeded then GS will result. We will test this hypothesis by developing a mouse transgenic model where degree of podocyte depletion can be determined at will and resu;lting GS measured directly (Aim 1).
In Aim 2 we will use rat models to test the hypothesis that podocyte number in relation to glomerular area determines the onset of GS in aging and renal depletion.
Aim 3 will evaluate human renal biopsies to establish normal ranges GAPP for age, sex and race and to determine whether diseases associated with GS in man have similar relative podocyte depletion. The identification of podocyte depletion as a major mechanism underlying glomerulosclerosis will be an important step towards development of improved strategies for prevention of progression, new monitoring strategies and new treatments for glomerulosclerosis.
| 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 |
| 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 |
| 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 |
| 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 |
| Naik, Abhijit S; Afshinnia, Farsad; Cibrik, Diane et al. (2016) Quantitative podocyte parameters predict human native kidney and allograft half-lives. JCI Insight 1: |
| 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 |
| Yang, Yan; Hodgin, Jeffrey B; Afshinnia, Farsad et al. (2015) The two kidney to one kidney transition and transplant glomerulopathy: a podocyte perspective. J Am Soc Nephrol 26:1450-65 |
Showing the most recent 10 out of 25 publications
