Unknown,Transcriptomics,Genomics,Proteomics

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Kidney Stone Induces Developmental Stage-specific Alterations in Gene Expression

ABSTRACT: OBJECTIVES: Kidney stone diseases are common in premature infants, but the underlying molecular and cellular mechanisms are not fully defined. We carried out a prospective observational study using microarray analysis to identify factors that may be crucial for the initiation and progression of stone-induced injury in the developing mouse kidney. METHODS: Mice with adenine phosphoribosyltransferase (Aprt) deficiency develop 2,8-dihydroxyadenine (DHA) nephrolithiasis. Gene expression changes between Aprt-/- and Aprt+/+ kidneys from newborn and adult mice were compared using Affymetrix gene chips. RESULTS: We observed that: (i) gene expression changes induced by Aprt deficiency are developmental stage-specific; (ii) maturation-related gene expression changes are delayed in developing Aprt-/- kidneys; and (iii) immature Aprt-deficient kidneys contain large numbers of intercalated cells blocked from terminal differentiation. CONCLUSIONS: This study presents a comprehensive picture of the transcriptional changes induced by stone injury in the developing mouse kidney. Our findings help explain growth impairment in kidneys subject to injury during the early stages of development. Total RNA were extracted from kidneys of 12 newly born and 6 adult mice (half Aprt-/- and half control). Gene expression changes between Aprt-/- and Aprt+/+ kidneys from newborn and adult mice were compared using Affymetrix gene chips.

ORGANISM(S): Mus musculus

SUBMITTER: Jianmin Chen

PROVIDER: E-GEOD-18160 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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2,8-dihydroxyadenine nephrolithiasis induces developmental stage-specific alterations in gene expression in mouse kidney.

Chen Jianmin J Chen Yanping Y Capizzi Stephanie S Yang Min M Deng Li L Bledsoe Sharon B SB Evan Andrew P AP Tischfield Jay A JA Sahota Amrik A

Urology 20091229 4

<h4>Objectives</h4>To identify factors that may be crucial for the initiation and progression of stone-induced injury in the developing mouse kidney by a prospective observational study using microarray analysis. Kidney stone diseases are common in premature infants, but the underlying molecular and cellular mechanisms are not fully defined.<h4>Methods</h4>Mice with adenine phosphoribosyltransferase deficiency develop 2,8-dihydroxyadenine (DHA) nephrolithiasis. The gene expression changes betwee ...[more]

PMID: 20035974

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Project description:Fibroblasts are present in every organ. While the role fibroblasts in chronic diseases such as fibrosis or tumor expression has been extensively explored, little is known about their physiological role. The kidney possesses a unique capacity to recover from even severe acute injury. We study molecular mechanisms of this intrinsic repair capacity in the mouse model of ischemia-reperfusion (IR). In this model, the renal artery and vein are clamped for 45 min, leading to acute kidney injury. The kidney spontaneously recovers from such IR injury within 14 days. IR kidney injury is associated with a transient accumulation of fibroblasts in the diseased tissue. We hypothesized that fibroblasts aid the repair of acute IR injury in the kidney. To elucidate how FSP1+ fibroblasts may contribute to the repair of kidney injury, we undertook a global unbiased approach to compare gene expression profiles of fibroblasts isolated from kidneys post-IRI and from control kidneys by FACS sorting. To investigate the role fibroblasts may play in the repair of kidney inhury, we performed ischemia reperfusion injury surgery on transgenic mice in which the FSP-1 promoter drives EGFP expression. Kidney injury peaks at day 3 post-IRI, followed by spontaneous regeration that restores nearly perfect kidney architecture and health by day 10. Fibroblasts are thought to possibly play a role in this process, as they are normally rare in the healthy kidney, acute kidney injury is associated with a transient accumulation of interstitial fibroblasts, but whether they may help repair the acute kidney injury or in fact could contribute to the damage is not known. To compare the gene expression profiles of normal fibroblasts and those from post-ischemic kidneys, we sacrificed control FSP1-GFP mice and the FSP1-GFP mice three days post-IRI. We generated single-cell suspensions from both the post-IRI and control kidneys, and then isolated FSP1-GFP+ cells by FACS sorting that, when cultured on plastic, displayed typical fibroblast morphology. Total RNA was immediately extracted from the sorted cells and amplified to produce enough for a array. We biotinylated five of the samples from post-ischemic kidneys and three of the control (non-ischemic) kidneys and used Affymetrix 3' Arrays to examine differences in gene expression profiles between the two groups that may she some light on what role, if any, fibroblasts play in the spontaneous healing of the kidney after acute kidney injury. We performed ischemia reperfusion surgery in FSP1-GFP mice, and at day 3, we sacrificed the mice, isolated FSP1-GFP positive cells from both IR and normal control kidneys by FACS sorting, extracted total RNA from the isolated FSP1-GFP cells and used Affymetrix Mouse Expression Array 430 2.0 microarrays to perform gene expression profiling of the samples. All told, we performed the FACS Sorting, RNA extration, and hybridization with 5 ischemic kidneys and 3 normal kidneys. Fibroblasts, acute kidney injury, repair, comparative gene expression profiling, microarrays, FACS sorting, role in healing

Dataset Information

Kidney Stone Induces Developmental Stage-specific Alterations in Gene Expression

Publications

2,8-dihydroxyadenine nephrolithiasis induces developmental stage-specific alterations in gene expression in mouse kidney.

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