The Wiggins laboratory has focused on the concept that all glomerular diseases can be considered as a spectrum of podocytopathies in which progression is associated with net depletion of podocytes from glomerular tufts (“The Podocyte Depletion Hypothesis”). Specifically he has developed novel model systems to define how podocyte depletion can be initiated by podocyte loss, dysfunction, or by glomerular enlargement due to growth and glomerular hypertrophy. Each of these events leads to net podocyte depletion. Once a critical degree of podocyte depletion has occurred the glomerulus then becomes destabilized leading to angiotensin 2-dependent further podocyte loss until global podocyte depletion occurs at End Stage Kidney Disease. He has developed a novel approach to measure podocyte density and number per glomerular tuft that is applicable to archival biopsy samples and is relatively high throughput for analysis for clinical studies. In parallel the Wiggins laboratory developed, validated and tested urine pellet mRNA assays in model systems humans. These studies prove that all glomerular diseases are associated with an increased rate of podocyte detachment into the urine and that progression is associated with high levels of podocyte detachment. Initial application of these tools to clinical samples provides remarkable insights into progression of glomerular disease with age, kidney transplantation, and in specific glomerular diseases (including diabetes, FSGS, Alport Syndrome, Membranous GN, Lupus nephritis and other conditions). These data support the concept that application of these principles to day-to-day care of patients could significantly improve clinical decision-making. Current research is directed at optimizing application of these principles to decision-making in the clinic.
Link to PubMed Citations
Venkatareddy M, Wang SQ, Yang Y, Patel S, Wickman L, Nishizono R, Chowdhury M, Hodgin J, Wiggins PA and Wiggins RC Estimating podocyte number and density in histologic sections. J Am Soc Nephrol. 2014. [E-pub ahead of print].
Wickman L, Afshinnia F, Yang Y, Wang SQ, Wang F, Chowdhury M ,Graham D, Hawkins J, Nishizono R, Tanzer M, Wiggins J ,Escobar GA, Rovin B , Song P, Gipson D, Kershaw D, Wiggins RC. Urine podocyte mRNAs, proteinuria and progression in human glomerular diseases. J Am Soc Nephrol. 24:2081-95. 2013
Ashraf S, Gee HY,1 Woerner S, XieLX, Vega-Warner V,Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschké P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou W, Airik R, Otto E, Barua M, Al-Hamed MH, Kari JK, Evans J, Bierzynska A, Saleem MA, Böckenhauer D, Kleta R, El DesokyS, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton R, Levy S, Han Z,Salviati S, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, and Hildebrandt F. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. 123:5179-89, 2013.
Gee, HY, Ashraf S, Saisawat P, Hurd TW Vega-Warner V, Fang H, Beck B, Gribouval O, Zhou W, Diaz K, Natarajan S, Wiggins RC, Lovric S, Chernin G, Schoeb DS, Ovunc B, Frishberg Y, Soliman NA, Fathy HM, Goebel H, Hoefele J, Weber LT, Innis JW, Faul C, Washburn Antignac JC, Levy S, Otto EA, and Hildebrandt F. ARHGDIA mutations cause nephrotic syndrome by defective RHO GTPase signaling. J Clin Invest. 123:3243-53, 2013
Fukuda A, Chowdhury M, Venkatareddy M, Wang SQ, Nishizono R, Wickman L, Wiggins J, Muchayi T, Fingar D, Shedden K, Inoki K and Wiggins RC. Growth-dependent podocyte failure causes glomerulosclerosis. J Am Soc Nephrol. 23:1351-63, 2012
Inoki K, Mori H, Wang J, Suzuki T, Hong SK, Yoshida S, Blattner , Ikenoue T, Rüegg M, Hall M, Kwiatkowski D, Rastaldi M, Huber T, Kretzler M, Holzman L, Wiggins RC, Guan K-L. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy J Clin Invest. 121: 2181-96, 2011
Fukuda A, Wickman LT, Venkatareddy M, Sato Y, Chowdhury M, Wang SQ, Shedden K, Dysko R, Wiggins J and Wiggins RC. Progression is caused by angiotensin II-dependent persistent podocyte loss from destabilized glomeruli. Kidney Int. 81:40-55, 2011.
Heeringa S, Chernin G, Chaki M, Zhou W, Sloan A, Ji Z, Letian X, Salviati L, Hurd T, Vega-Warner V, Killen P, Raphael Y, Ashraf S, Ovunc B, Schoeb D, McLaughlin H, Airik R, Vlangos C, Gbadegesin R, Hinkes B, Saisawat1 P, Trevisson P, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rötig A, Corinne Antignac C, Nurnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu S, Müller d, Beissert A, Mir S, Berdeli A, Özen S, Zenker M, Matejas V, Ocana C, Navas P, Kusakabe T, Kispert A, Soliman N, Krick S, Mundel P, Reiser J, Nurnberg P, Clarke C, Wiggins RC, Faul C, Hildebrandt F. COQ6 mutations cause nephrotic syndrome with sensorineural deafness in parallel with increased apoptosis J Clin Invest. 121:2013-2024, 2011
Fukuda A and Wiggins RC. Podocyte biomarkers in urine: Relevance and potential. J Clin Metab and Diabetes.. 2:39-44, 2011.
Wiggins JE, Patel S, Shedden K, Goyal M, Wharram B , Martini S, Kretzler M and Wiggins RC. NFkB in the pro-inflammatory, pro-coagulant, pro-fibrotic aging glomerulus. J Am Soc Nephrol. 21::587-97, 2010
O’Toole J, Davis E, Westlake C, Attanasio M, Otto EA, Seelow D, Nurnberg G, Becker C, Nuutinen M, Kärppä M, Ignatius J, Uusimaa J, Pakanen S, Jaakkola E, van den Heuvel L, Fehrenbach H, Wiggins RC, Goyal M, Zhou W, Wolf M, Wise E, Helou J, Allen S, Zamalloa C, Moumita Chaki A, Heeringa S, Chernin G, Hoskins B, Chaib H, Gleeson J, Kusakabe T, Suzuki T, Isaac RE, Quarmby L, Tennant B, Fujioka H, Tuominen H, Hassinen I, Lohi H, van Houten JL, Rotig A, Sayer JA, Rolinski B, Freisin P, Biste M, Madignier F, Prokisch H, Nurnberg P, Jackson P, Khanna H, Katsanis N and Hildebrandt F. Mutations in XPNPEP3, encoding a mitochondrial protein, cause a nephronophthisis-like nephropathy. J. Clin Invest. 120:791-802. 2010
Sato Y, Wharram B, S Lee SK, Wickman L, Goyal M, Venkatareddy M, Chang JW, Wiggins J, Lienczewski C, Kretzler M and Wiggins RC. Urine podocyte mRNAs mark progression of renal disease. J Am Soc Nephrol. 20:1041-52, 2009.
Wiggins RC. The spectrum of podocytopathies. A unifying view of glomerular diseases. Kidney Int. 71:1205-1214, 2007
Hinkes B*, Wiggins RC* (co-equal first authors), Gbadegesin R, Vlangos C, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins B, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram B, , Schacter A, Drummond I, Kerjaschki D, Waldherr R, Deitrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin A, Soylu A, Muller D, Katan M, Liu J, Attanasio M, O’Toole J, Hasselbacher K, Mucha B, Otto E, Airik R, Kispert A, Kelley G, Smrcka A, Gudermann T, Holzman L, Nurnberg P, Hildebrandt F. Positional cloning of PLCE1 mutations as the first cause of a nephrotic syndrome variant which may be reversible. Nature Genetics. 38:1397-405, 2006
Wiggins J, Goyal M, Sanden S, Wharram B, Shedden K, Misek D, Kuick R, Wiggins RC. Podocyte hypertrophy, “adaptation” and “decompensation” associated with glomerular enlargement and glomerulosclerosis in the aging rat: Prevention by calorie restriction. J Am Soc Nephrol 16:2953-2966, 2005
Wharram B, Goyal M, Wiggins J, Sanden S, Hussain S, Filipiak W, Saunders T, Dysko R, Kohno K, Holzman L, Wiggins RC. Podocyte depletion causes glomerulosclerosis. Diphtheria toxin-induced podocyte depletion in rats expressing the human DTR transgene. J Am Soc Nephrol 16:2941-2952, 2005
Sanden SK, Wiggins JE, Goyal M, Riggs LK, Wiggins RC. A thick and thin section method for estimation of podocyte number in rat kidney using WT-1 as a podocyte nuclear marker. J Am Soc Nephrol 14:2484-2493, 2003.
Moeller MJ, Sanden SK, Soofi A, Wiggins RC, Holzman LB. Podocyte-specific expression of Cre recombinase in transgenic mice. Genesis 55:39-42, 2003