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PLoS One. 2019 Oct 3;14(10):e0222948. doi: 10.1371/journal.pone.0222948. eCollection 2019.

Identification of glomerular and podocyte-specific genes and pathways activated by sera of patients with focal segmental glomerulosclerosis.

Author information

1
Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
2
Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
3
Department of Internal Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida, United States of America.
4
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
5
Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
6
Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
7
Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
8
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

Abstract

Focal segmental glomerulosclerosis (FSGS) accounts for about 40% of all nephrotic syndrome cases in adults. The presence of several potential circulating factors has been suggested in patients with primary FSGS and particularly in patients with recurrent disease after transplant. Irrespectively of the nature of the circulating factors, this study was aimed at identifying early glomerular/podocyte-specific pathways that are activated by the sera of patients affected by FSGS. Kidney biopsies were obtained from patients undergoing kidney transplantation due to primary FSGS. Donor kidneys were biopsied pre-reperfusion (PreR) and a subset 1-2 hours after reperfusion of the kidney (PostR). Thirty-one post reperfusion (PostR) and 36 PreR biopsy samples were analyzed by microarray and gene enrichment KEGG pathway analysis. Data were compared to those obtained from patients with incident primary FSGS enrolled in other cohorts as well as with another cohort to correct for pathways activated by ischemia reperfusion. Using an ex-vivo cell-based assay in which human podocytes were cultured in the presence of sera from patients with recurrent and non recurrent FSGS, the molecular signature of podocytes exposed to sera from patients with REC was compared to the one established from patients with NON REC. We demonstrate that inflammatory pathways, including the TNF pathway, are primarily activated immediately after exposure to the sera of patients with primary FSGS, while phagocytotic pathways are activated when proteinuria becomes clinically evident. The TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS supports prior experimental findings from our group demonstrating a causative role of local TNF in podocyte injury in FSGS. Correlation analysis with clinical and histological parameters of disease was performed and further supported a possible role for TNF pathway activation in FSGS. Additionally, we identified a unique set of genes that is specifically activated in podocytes when cultured in the presence of serum of patients with REC FSGS. This clinical translational study supports our prior experimental findings describing a potential role of the TNF pathway in the pathogenesis of FSGS. Validation of these findings in larger cohorts may lay the ground for the implementation of integrated system biology approaches to risk stratify patients affected by FSGS and to identify novel pathways relevant to podocyte injury.

PMID:
31581251
DOI:
10.1371/journal.pone.0222948
Free PMC Article

Conflict of interest statement

G.W.B., A.F., and S. Merscher. are inventors on pending or issued patents aimed to diagnose or treat proteinuric renal diseases. They stand to gain royalties from their future commercialization. A.F. is Chief Scientific Officer of L&F Health LLC and is consultant for Variant Pharmaceutical. Variant Pharmaceuticals, Inc. has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for treatment of kidney disease from L&F Research. A.F. is Chief Scientific Officer for LipoNexT LLC. S. Merscher holds equity interest in L&F Research. Grant funding to support the work has been received by the U Michigan in support of the work performed by M.K. from the National Institute of Health, European Union, Else Kroener Fresenius Foundation, Nephcure Kidney International, Eli Lilly and Goldfinch Bio. These funding bodies did not had influence on study design; collection, analysis, and interpretation of data; writing of the paper; and/or decision to submit for publication. S.E. has declared stock ownership from Thermo Fisher Scientific, Johnson and Johnson and Gilead Sciences and former employment by Thermo Fisher Scientific, Johnson and Johnson. L.O., E.C., D.W., V.N., M.C., P.R., P.W., L.T. have declared no competing interests. Any of the existing conflicts do not alter our adherence to PLOS ONE policies on sharing data and materials.

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