title: The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.
abstract: IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.affiliation: Department of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.affiliation: Department of Laboratory Medicine and Pathology, University Health Network and University of Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathology, University Health Network and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rohan
authors.initials: R
authors.lastname: John
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Grone
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Department of Laboratory Medicine and Pathology, University Health Network and University of Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathology, University Health Network and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Herzenberg
authors.affiliation: Department of Medicine, University Health Network and University of Toronto, and the Toronto Glomerulonephritis Registry, Toronto, Ontario, Canada.
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
authors.affiliation: Department of Nephrology, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada; Department of Medicine, University Health Network and University of Toronto, and the Toronto Glomerulonephritis Registry, Toronto, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hladunewich
authors.affiliation: Department of Medicine, University Health Network and University of Toronto, and the Toronto Glomerulonephritis Registry, Toronto, Ontario, Canada.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Cattran
authors.affiliation: Department of Internal Medicine, Nephrology, and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: Department of Medicine, University Health Network and University of Toronto, and the Toronto Glomerulonephritis Registry, Toronto, Ontario, Canada.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Reich
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D005260:Female; D005922:Glomerulonephritis, IGA / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010641:Phenotype; D059467:Transcriptome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones