research
mission
Our research program seeks to define key signaling pathways essential for cellular homeostasis with the overarching goal of developing novel therapeutic options for patients with kidney disease.
our Research
1. Identification of key mediators of podocyte injury and loss.
Our group showed that the glomerular slit diaphragm molecule dendrin shuttled to the podocyte nucleus to promote apoptosis. We subsequently showed that dendrin gene deletion slowed the progression of glomerular disease in CD2AP null mice by inhibiting podocyte injury and podocyte-mesangial cell crosstalk. We also demonstrated the role of fatty acid induced podocyte injury mediated by endoplasmic reticulum stress.
a. Asanuma, K., Campbell, K.N. (co-first author), Faul, C, Kim K and Mundel, P. Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. Proc Natl Acad Sci. 2007. 104:10134-10139
b. Weins, A, Wong, J.S., Basgen, J., Gupta, R., Daehn, I, Casagrande, L., Lessman, D., Schwartzman, L., Meliambro, K., Patrakka, J., Shaw, A., Tryggvason, K., He, J.C., Nicholas, S, Mundel, P. and Campbell, K.N. Dendrin ablation prolongs life span by delaying renal failure. Am J Pathol 2015. Aug 185 (8): 2143-57
c. Shirata N, Ihara KI, Yamamoto-Nonaka K, Seki T, Makino SI, Oliva Trejo JA, Miyake T, Yamada H, Campbell KN, Nakagawa T, Mori K, Yanagita M, Mundel P, Nishimori K, Asanuma K. Glomerulsclerosis Induced by Deficiency of Membrane-Associated Guanylate Kinase Inverted 2 in Kidney Podocytes. J Am Soc Nephrol. 2017 Sep; 28 (9): 2654-2669
d. Calizo R, Bhattacharya S, Coen van Hasselt JG, Wei C, Wong JS, Wiener RJ, Ge X,
Wong NJ, Lee J, Cuttitta CM, Jayaraman G, Au VH, Janssen W, Li H, Salem F, Jaimes EA, Murphy B, Campbell, KN, Azeloglu, EU. “Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity”. Nat Commun (2019). In Press
2. Hippo-YAP signaling pathway in podocyte survival and beyond.
The Hippo pathway controls organ size and cell survival in model systems most extensively studied in the cancer field. Our group has identified a role for Hippo signaling in podocytes where we found that its effector molecule YAP is a dendrin inhibitor essential for maintaining an intact glomerular filter.
a. Campbell, K.N., Wong, J.S., Gupta, R., Asanuma, K., Sudol, M, He, J.C., and Mundel, P. YAP promotes cell survival by inhibiting pro-apoptotic dendrin signaling. J. Biol. Chem. 2013 June 14;288 (24):17057-62.
b. Schwartzman, M, Reginensi, A, Wong, J, Basgen, J, Meliambro K., Nicholas, S., D’Agati, V, McNeill, H and Campbell, K.N. Podocyte-specific deletion of Yes-associated protein causes focal segmental glomerulosclerosis and progressive renal failure. J Am Soc Neph. 2016. Jan; 27(1):216-26
c. Meliambro, K., Wong JS, Ray, J, Calizo, R, Towne, S, Cole, B, Salem, F., Gordon, R, Kaufman, L, He, JC, Azeloglu, E and Campbell KN. The Hippo Pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics. J Biol Chem. 2017. Dec 22, 292 (51): 21137-21148
d. Lee, YA, Noon LA, Lee T, Akat, KM, Chou HI, Berres ML, Fiel MI, Gordon R, Pfleger, C, Germain D, Khambu B, Yin XM, Campbell KN, Yue Z, Elisabeth Kramer E, John G, Czaja MJ, Hoshida Y, and Friedman SL. Autophagy is a gatekeeper of differentiation and hepatocarcinogenesis by controlling degradation of Yap. Nat Comm. 2018. Nov 23;9(1):4962
3. Actin cytoskeleton dynamics and integrin-mediated adhesion in podocyte homeostasis:
Podocytes are terminally differentiated cells with a limited capacity to regenerate. Their role as the key target cell for injury in proteinuric kidney disease coupled with a lack of cell-specific therapy for clinical use makes understanding their complex molecular architecture essential. Our work has contributed significantly to the identification of the actin bundling molecule synaptopodin as a target of cyclosporine, and clarified the role of B7-1 and Rap1GAP in podocyte adhesion and motility
a. Faul, C, Donnelly, M., Chang, Y.H., Franz, F., Merscher-Gomez, S., Delfgaauw, J., Chang, J.M., Choi, H.Y., Campbell, K.N., Kim, K, Reiser, J., and Mundel, P. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008 Sep;14(9):931-8
b. Yu C, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, Chen L, Ciancio G, M.D., Faridi MH, Behr D, Campbell KN, Chang JM, Chen HC, Oh J, Faul C, Arnaout MA, Fiorina P, Gupta V, Greka A, Burke G, M.D., and Mundel P. Abatacept in B7-1 Positive Proteinuric Kidney Disease. N Engl J Med. 2013 Dec 19;369(25):2416-23.
c. Potla, U, Ni, J, Vadaparampil, J, Yang, G, Leventhal, J, Campbell, K.N., Chuang, P, Morozov, A, He, JC, D’Agati, V, Klotman, P and Kaufman, L. Increased Rap1GAP expression in podocytes contributes to glomerular injury in FSGS. J. Clin. Invest. 2014; 124 (4): 1757-69
d. Wei C, Banu K, Garzon F, Basgen JM, Philippe N, Yi Z, Liu R, Choudhuri J, Fribourg M, Liu T, Cumpelik A, Wong J, Khan M, Das B, Keung K, Salem F, Campbell KN, Kaufman L, Cravedi, P, Zhang W, O’Connell PJ, He JC, Murphy B and Menon MC. SHROOM3-FYN Interaction Regulates Nephrin Phosphorylation and Affects Albuminuria in Allografts. J Am Soc Neph. 2018 Nov; 29 (11): 2641-2657.
4. Novel therapeutics for glomerular disease:
A central goal is to improve treatment options for patients with glomerular disease. Given lack of FDA approved therapies for conditions like FSGS we have participated in clinical trials designed to test the efficacy and safety of promising new therapies
a. Vicenti, F., Fervenza, F., Campbell, K.N., Diaz, M. Gesualdo, L, Nelson, P., Praga, M, Radhakrishnan, J., Sellin, L., Singh, A, Thornley-Brown, D, Vernese, FV, Accomomado, B., Engstrand, S., Ledbetter, S., Lin, J, Neylan, J., Tumlin J. and the FSGS Study Group. A phase 2, double blind, placebo-controlled, randomized study of fresolimumab on patients with steroid-resistant primary focal segmental glomerulosclerosis. Kidney Int Rep, 2017 Apr 7 (5): 800-810
b. Trachtman, H, Nelson, P, Adler H, Campbell, KN, Chaudhuri, A, Derebail, V, Gambaro, G, Gesualdo, L, Gipson, D, Hogan, J, Lieberman, K, Marder, B, Meyers, K, Mustafa, E, Radhakrishnan, J, Srivastava, T, Stepanians, M, Tesar, V, Zhdanova, O and Komers R. Efficacy and Safety of Sparsentan in Patients with Focal Segmental Glomerulosclerosis: A Randomized, Active-Controlled, Phase 2 Trial (DUET). J Am Soc Nephrol 2018. Nov; 29 (11):2745-2754
c. Hartzell S, Sanchez-Russo L, Perez-Pecchio I, Okoroafor I, MD1 Meliambro K, Fribourg M, Cantarelli C, Campbell, KN, Cravedi P. Repository Corticotropin Injection Promotes Clinical Remission and Treg Expansion in Membranous Nephropathy. KI Reports 2021. Jun 22;6(9):2491-2495.