Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.

<h4>Background</h4>In patients with Type 1 Diabetes (T1D) who develop microalbuminuria, progressive decline in glomerular filtration rate (GFR) may be initiated by leakage into the urine of toxic proteins (txUPs). This study tested this hypothesis.<h4>Methods</h4>After archiv...

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Autores principales:	Krzysztof Wanic, Bozena Krolewski, Wenjun Ju, Grzegorz Placha, Monika A Niewczas, William Walker, James H Warram, Matthias Kretzler, Andrzej S Krolewski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f597fa36f62144ebb25c77ef229f080d
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spelling	oai:doaj.org-article:f597fa36f62144ebb25c77ef229f080d2021-11-18T07:54:26ZTranscriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.1932-620310.1371/journal.pone.0057751https://doaj.org/article/f597fa36f62144ebb25c77ef229f080d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23505438/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>In patients with Type 1 Diabetes (T1D) who develop microalbuminuria, progressive decline in glomerular filtration rate (GFR) may be initiated by leakage into the urine of toxic proteins (txUPs). This study tested this hypothesis.<h4>Methods</h4>After archiving baseline urine, we followed T1D patients with microalbuminuria for 8-12 years to distinguish those in whom GFR declined (Decliners) and those in whom it remained stable (Non-decliners). Human proximal tubular cells (HK-2 cells) were grown in serum-free medium enriched with pooled urines from Decliners or Non-decliners. We determined genome-wide expression profiles in extracted mRNA.<h4>Results</h4>The two pooled urines induced differential expression of 312 genes. In terms of gene ontology, molecular functions of the 119 up-regulated genes were enriched for protein binding and peptidase inhibitor activities. Their biologic processes were enriched for defense response, responses to other organisms, regulation of cellular processes, or response to stress or stimulus, and programmed cell death. The 195 down-regulated genes were disproportionately represented in molecular functions of cation binding, hydrolase activity, and DNA binding. They were disproportionately represented in biological processes for regulation of metabolic processes, nucleic acid metabolic processes, cellular response to stress and macromolecule biosynthesis. The set of up-regulated genes in HK-2 cells overlaps significantly with sets of over-expressed genes in tubular and interstitial compartments of kidney biopsies from patients with advanced DN (33 genes in one study and 25 in the other compared with 10.3 expected by chance, p<10(-9) and p<10(-4), respectively). The overlap included genes encoding chemokines and cytokines. Overlap of down-regulated genes was no more than expected by chance.<h4>Conclusions</h4>Molecular processes in tubules and interstitium seen in advanced diabetic nephropathy can be induced in vitro by exposure to urine from patients with minimal microalbuminuria who subsequently developed progressive renal function decline, presumably due to putative txUPs.Krzysztof WanicBozena KrolewskiWenjun JuGrzegorz PlachaMonika A NiewczasWilliam WalkerJames H WarramMatthias KretzlerAndrzej S KrolewskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e57751 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Krzysztof Wanic Bozena Krolewski Wenjun Ju Grzegorz Placha Monika A Niewczas William Walker James H Warram Matthias Kretzler Andrzej S Krolewski Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
description	<h4>Background</h4>In patients with Type 1 Diabetes (T1D) who develop microalbuminuria, progressive decline in glomerular filtration rate (GFR) may be initiated by leakage into the urine of toxic proteins (txUPs). This study tested this hypothesis.<h4>Methods</h4>After archiving baseline urine, we followed T1D patients with microalbuminuria for 8-12 years to distinguish those in whom GFR declined (Decliners) and those in whom it remained stable (Non-decliners). Human proximal tubular cells (HK-2 cells) were grown in serum-free medium enriched with pooled urines from Decliners or Non-decliners. We determined genome-wide expression profiles in extracted mRNA.<h4>Results</h4>The two pooled urines induced differential expression of 312 genes. In terms of gene ontology, molecular functions of the 119 up-regulated genes were enriched for protein binding and peptidase inhibitor activities. Their biologic processes were enriched for defense response, responses to other organisms, regulation of cellular processes, or response to stress or stimulus, and programmed cell death. The 195 down-regulated genes were disproportionately represented in molecular functions of cation binding, hydrolase activity, and DNA binding. They were disproportionately represented in biological processes for regulation of metabolic processes, nucleic acid metabolic processes, cellular response to stress and macromolecule biosynthesis. The set of up-regulated genes in HK-2 cells overlaps significantly with sets of over-expressed genes in tubular and interstitial compartments of kidney biopsies from patients with advanced DN (33 genes in one study and 25 in the other compared with 10.3 expected by chance, p<10(-9) and p<10(-4), respectively). The overlap included genes encoding chemokines and cytokines. Overlap of down-regulated genes was no more than expected by chance.<h4>Conclusions</h4>Molecular processes in tubules and interstitium seen in advanced diabetic nephropathy can be induced in vitro by exposure to urine from patients with minimal microalbuminuria who subsequently developed progressive renal function decline, presumably due to putative txUPs.
format	article
author	Krzysztof Wanic Bozena Krolewski Wenjun Ju Grzegorz Placha Monika A Niewczas William Walker James H Warram Matthias Kretzler Andrzej S Krolewski
author_facet	Krzysztof Wanic Bozena Krolewski Wenjun Ju Grzegorz Placha Monika A Niewczas William Walker James H Warram Matthias Kretzler Andrzej S Krolewski
author_sort	Krzysztof Wanic
title	Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
title_short	Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
title_full	Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
title_fullStr	Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
title_full_unstemmed	Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
title_sort	transcriptome analysis of proximal tubular cells (hk-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f597fa36f62144ebb25c77ef229f080d
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Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline.

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