Functional genomic analysis identifies indoxyl sulfate as a major, poorly dialyzable uremic toxin in end-stage renal disease

Sachin Jhawar, Prabhjot Singh, Daniel Torres, Francisco Ramirez-Valle, Hania Kassem, Trina Banerjee, Igor Dolgalev, Adriana Heguy, Jiri Zavadil, Jerome Lowenstein

Research output: Contribution to journalArticle

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Abstract

Background: Chronic renal failure is characterized by progressive renal scarring and accelerated arteriosclerotic cardiovascular disease despite what is considered to be adequate hemodialysis or peritoneal dialysis. In rodents with reduced renal mass, renal scarring has been attributed to poorly filtered, small protein-bound molecules. The best studied of these is indoxyl sulfate (IS). Methods: We have attempted to establish whether there are uremic toxins that are not effectively removed by hemodialysis. We examined plasma from patients undergoing hemodialysis, employing global gene expression in normal human renal cortical cells incubated in pre- and post- dialysis plasma as a reporter system. Responses in cells incubated with pre- and post-dialysis uremic plasma (n = 10) were compared with responses elicited by plasma from control subjects (n = 5). The effects of adding IS to control plasma and of adding probenecid to uremic plasma were examined. Plasma concentrations of IS were measured by HPLC (high pressure liquid chromatography). Results: Gene expression in our reporter system revealed dysregulation of 1912 genes in cells incubated with pre-dialysis uremic plasma. In cells incubated in post-dialysis plasma, the expression of 537 of those genes returned to baseline but the majority of them (1375) remained dysregulated. IS concentration was markedly elevated in pre- and post-dialysis plasma. Addition of IS to control plasma simulated more than 80% of the effects of uremic plasma on gene expression; the addition of probenecid, an organic anion transport (OAT) inhibitor, to uremic plasma reversed the changes in gene expression. Conclusion: These findings provide evidence that hemodialysis fails to effectively clear one or more solutes that effect gene expression, in our reporter system, from the plasma of patients with uremia. The finding that gene dysregulation was simulated by the addition of IS to control plasma and inhibited by addition of an OAT inhibitor to uremic plasma identifies IS as a major, poorly dialyzable, uremic toxin. The signaling pathways initiated by IS and possibly other solutes not effectively removed by dialysis may participate in the pathogenesis of renal scarring and uremic vasculopathy.

Original languageEnglish (US)
Article numbere0118703
JournalPLoS One
Volume10
Issue number3
DOIs
StatePublished - Mar 26 2015
Externally publishedYes

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Indican
dialysis
kidney diseases
Chronic Kidney Failure
sulfates
toxins
Dialysis
Plasmas
genomics
hemodialysis
kidneys
gene expression
Gene expression
Renal Dialysis
anions
Kidney
Gene Expression
solutes
Cicatrix
Probenecid

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Functional genomic analysis identifies indoxyl sulfate as a major, poorly dialyzable uremic toxin in end-stage renal disease. / Jhawar, Sachin; Singh, Prabhjot; Torres, Daniel; Ramirez-Valle, Francisco; Kassem, Hania; Banerjee, Trina; Dolgalev, Igor; Heguy, Adriana; Zavadil, Jiri; Lowenstein, Jerome.

In: PLoS One, Vol. 10, No. 3, e0118703, 26.03.2015.

Research output: Contribution to journalArticle

Jhawar, S, Singh, P, Torres, D, Ramirez-Valle, F, Kassem, H, Banerjee, T, Dolgalev, I, Heguy, A, Zavadil, J & Lowenstein, J 2015, 'Functional genomic analysis identifies indoxyl sulfate as a major, poorly dialyzable uremic toxin in end-stage renal disease', PLoS One, vol. 10, no. 3, e0118703. https://doi.org/10.1371/journal.pone.0118703
Jhawar, Sachin ; Singh, Prabhjot ; Torres, Daniel ; Ramirez-Valle, Francisco ; Kassem, Hania ; Banerjee, Trina ; Dolgalev, Igor ; Heguy, Adriana ; Zavadil, Jiri ; Lowenstein, Jerome. / Functional genomic analysis identifies indoxyl sulfate as a major, poorly dialyzable uremic toxin in end-stage renal disease. In: PLoS One. 2015 ; Vol. 10, No. 3.
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AU - Ramirez-Valle, Francisco

AU - Kassem, Hania

AU - Banerjee, Trina

AU - Dolgalev, Igor

AU - Heguy, Adriana

AU - Zavadil, Jiri

AU - Lowenstein, Jerome

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