The presence of a circulating factor that increases glomerular macromolecular permeability in patients with focal sclerosing glomerulonephritis (FSGS) is supported by recurrence of proteinuria in the immediate post-transplant period and by the observation that plasmapheresis is often effective in reversing this proteinuria. Attempts to identify the factor responsible for glomerular injury in FSGS have been largely unsuccessful. We have developed a sensitive in vitro assay for glomerular protein permeability and have employed this assay to demonstrate the presence of a factor in serum or plasma of patients with FSGS which increases glomerular macromolecular permeability. Incubation of glomeruli in media containing active sera increases albumin permeability from a normal value of 0 to as high as 0.9. The presence of this activity prior to transplantation is strongly associated with early recurrence of proteinuria and progressive renal insufficiency following renal transplantation. Preliminary studies suggest that the active component is a protein of molecular weight 110-120 kD. Its activity is rapid in onset and is concentration dependent. Activity is neutralized by the presence of normal serum; this finding may explain the difficulty that others have had in demonstrating its presence by infusion into intact animals. The goals of the proposed studies are: 1) to purify and characterize the albumin permeability enhancing factor from sera of FSGS patients using ammonium sulphate precipitation, gel filtration, ion exchange column chromatography, HPLC, gel electrophoresis and, if necessary, isoelectric focusing and capillary electrophoresis; 2) to determine the amino acid composition and amino acid sequence of the factor in order to compare it to known proteins. The availability of a bioassay for activity provides a unique opportunity to identify and characterize the factor responsible for proteinuria and, in later studies, to develop an immunologic assay for the factor, to identify its source, to define its targets and mechanism of action, and, finally, to develop rational and effective treatment for patients with FSGS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043752-03
Application #
2143253
Study Section
Pathology A Study Section (PTHA)
Project Start
1993-12-15
Project End
1996-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Sharma, Mukut; Zhou, Jianping; Gauchat, Jean-François et al. (2015) Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier. Transl Res 166:384-98
Srivastava, Tarak; Celsi, Gianni E; Sharma, Mukut et al. (2014) Fluid flow shear stress over podocytes is increased in the solitary kidney. Nephrol Dial Transplant 29:65-72
Charba, Deane S; Wiggins, Roger C; Goyal, Meera et al. (2009) Antibodies to protein tyrosine phosphatase receptor type O (PTPro) increase glomerular albumin permeability (P(alb)). Am J Physiol Renal Physiol 297:F138-44
Aggarwal, Nidhi; Batwara, Ruchika; McCarthy, Ellen T et al. (2007) Serum permeability activity in steroid-resistant minimal change nephrotic syndrome is abolished by treatment of Hodgkin disease. Am J Kidney Dis 50:826-9
Sharma, Mukut; McCarthy, Ellen T; Sharma, Ram et al. (2006) Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability. Exp Biol Med (Maywood) 231:99-106
Gohh, R Y; Yango, A F; Morrissey, P E et al. (2005) Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients. Am J Transplant 5:2907-12
Trachtman, Howard; Greenbaum, Laurence A; McCarthy, Ellen T et al. (2004) Glomerular permeability activity: prevalence and prognostic value in pediatric patients with idiopathic nephrotic syndrome. Am J Kidney Dis 44:604-10
Sharma, Mukut; Sharma, Ram; McCarthy, Ellen T et al. (2004) The focal segmental glomerulosclerosis permeability factor: biochemical characteristics and biological effects. Exp Biol Med (Maywood) 229:85-98
Cattran, Daniel; Neogi, Tuhina; Sharma, Ram et al. (2003) Serial estimates of serum permeability activity and clinical correlates in patients with native kidney focal segmental glomerulosclerosis. J Am Soc Nephrol 14:448-53
Savin, Virginia J; McCarthy, Ellen T; Sharma, Mukut (2003) Permeability factors in focal segmental glomerulosclerosis. Semin Nephrol 23:147-60

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