Podocyte foot processes (FPs) and the interposed slit diaphragm (SD) form the final barrier to protein loss, explaining why podocyte injury is typically associated with marked proteinuria. Podocyte dysfunction, represented by FP effacement, disruption of the SD and proteinuria, is often the starting point for progressive kidney disease. Here we propose to test our central hypothesis that the induction of hic-5 expression in podocytes contributes to the pathogenesis of proteinuria by increasing the adhesiveness of podocyte to the extracellular matrix (ECM)/glomerular basement membrane (GBM). We further hypothesize that the persistence of podocyte hic-5 expression in focal segmental glomerulosclerosis (FSGS) confers a senescence phenotype, thereby promoting the progression to ESRD. To test this hypothesis, we propose three Specific Aims.
The first Aim will define the molecular mechanism whereby hic-5 increases podocyte adhesion to the ECM, thereby altering cell motility, survival and senescence.
Specific Aim two seeks to test whether the induction of podocyte-specific hic-5 expression in mice causes proteinuria.
The third Aim will establish whether the prolonged expression of hic-5 in podocytes induces hypertrophy, senescence and apoptosis, thereby causing FSGS and progression to ESRD. If our hypothesis is correct, the work proposed here will have broad significance because it will provide us with a better understanding of the biological mechanism underlying the development of progressive proteinuric kidney diseases and offers a new target for the development of treatment strategies. This should in the long- term enable us to develop novel, podocyte-protective therapies that tackle proteinuric kidney diseases by suppressing the hic-5 mediated increased adhesion of podocytes to the GBM. Such hic-5 blocking compounds may also slow the progression of FSGS to ESRD by inhibiting the hic-5 mediated senescence of podocytes.
Our novel preliminary data, described in this grant application, identified a hic-5- dependent signaling pathway that contributes to the pathogenesis and progression of proteinuric kidney diseases by modulation podocyte adhesion to the extracellular matrix/glomerular basement membrane. The goal of this application is to define the molecular mechanisms whereby the modulation of hic-5 expression in podocytes causes proteinuria, thereby paving the road for the development of novel anti-proteinuric treatment options for which there is a critical need in the clinic.
|Yoon, Kyoung Wan; Byun, Sanguine; Kwon, Eunjeong et al. (2015) Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 349:1261669|
|Weins, Astrid; Wong, Jenny S; Basgen, John M et al. (2015) Dendrin ablation prolongs life span by delaying kidney failure. Am J Pathol 185:2143-57|
|Mundel, Peter; Greka, Anna (2015) Developing therapeutic 'arrows' with the precision of William Tell: the time has come for targeted therapies in kidney disease. Curr Opin Nephrol Hypertens 24:388-92|
|Hakroush, Samy; Cebulla, Angelika; Schaldecker, Thomas et al. (2014) Extensive podocyte loss triggers a rapid parietal epithelial cell response. J Am Soc Nephrol 25:927-38|
|Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29|
|Balbas, Minna D; Burgess, Michael R; Murali, Rajmohan et al. (2014) MAGI-2 scaffold protein is critical for kidney barrier function. Proc Natl Acad Sci U S A 111:14876-81|
|Yu, Chih-Chuan; Fornoni, Alessia; Weins, Astrid et al. (2013) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 369:2416-23|
|Buvall, Lisa; Rashmi, Priyanka; Lopez-Rivera, Esther et al. (2013) Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics. Nat Commun 4:2863|
|Greka, Anna; Mundel, Peter (2012) Calcium regulates podocyte actin dynamics. Semin Nephrol 32:319-26|
|Wong, Jenny S; Iorns, Elizabeth; Rheault, Michelle N et al. (2012) Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin ? in RhoA stabilization. EMBO J 31:1028-40|
Showing the most recent 10 out of 15 publications