Dataset Information

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

ABSTRACT: 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.Mice with adenine phosphoribosyltransferase deficiency develop 2,8-dihydroxyadenine (DHA) nephrolithiasis. The gene expression changes between Aprt(-/-) and Aprt(+/+) kidneys from newborn and adult mice were compared using Affymetrix gene chips. Targets of interest were further analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry.We identified a set of genes that were differentially expressed in the developing kidney in response to DHA-induced injury. In 1-week-old Aprt(-/-) mice, the expression of Sprr2f and Clu was highly augmented and that of Egf was significantly decreased. We also observed that maturation-related gene expression changes were delayed in developing Aprt(-/-) kidneys, and immature Aprt(-/-) kidneys contained large numbers of intercalated cells that were blocked from terminal differentiation.This study presents a comprehensive picture of the transcriptional changes induced by DHA stone injury in the developing mouse kidney. Our findings help explain growth impairment in kidneys subject to injury during the early stages of development.

SUBMITTER: Chen J

PROVIDER: S-EPMC3177599 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Similar Datasets

Project description:BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets