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Dehydration impaired normal renal development in infant mice

ABSTRACT: The kidney is a major organ in which fluid balance and waste excretion is regulated. To obtain mature functions of the kidney, normal renal developmental processes need to be preceded. Comprehensive genetic programs underlying renal development during prenatal life have been widely studied. However, postnatal renal development, from infancy to juvenile period, have not been studied yet. Here, we investigated if structural and functional kidney development was still undergoing in early life by analyzing renal transcriptional networks of infant (4 weeks old) and juvenile (7 weeks old) mice. We further examined the effects of dehydration on kidney development. Kidneys at 4 weeks and 7 weeks old showed significantly distinctive functional network of genes. Gene sets related to cell cycle regulators and immature glomerular barrier integrity (COL4A1, COL4A2) were enriched in infantile kidneys while genes associated with ion transport and drug metabolism (CYP450 family) were shown in juvenile kidneys. Dehydration during infancy suppressed renal growth by interrupting SHH signaling pathway which targets cell cycle regulators. Importantly, disruption of developmental program ultimately led to long-term alterations in renal filtration function, by causing a decline in glomerular filtration barrier integrity. Taken together, we provide meaningful perspectives of renal development in infancy which suggests molecular and physiological background why infants are more vulnerable to dehydration than adults. These results provide new insights into the systemic effects of dehydration on renal development and may propose possible markers for clinical application in pediatric dehydration.

ORGANISM(S): Mus musculus

PROVIDER: GSE75604 | GEO | 2016/07/01

SECONDARY ACCESSION(S): PRJNA304686

REPOSITORIES: GEO

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Project description:Gene expression profiling of kidneys from the murine model of HIV-associated nephropathy (HIVAN) identified an association between the expression of an endoplasmic reticulum (ER)-associated protein reticulon-1, RTN1, and the severity of kidney disease. Of the three known RTN1 isoforms, only RTN1A protein expression was increased in kidneys of murine models of HIVAN, diabetic nephropathy (DN), and renal fibrosis and humans with HIVAN and DN. Both mRNA and protein expression of RTN1-A in the kidneys correlated inversely with estimated glomerular filtration rate (eGFR) in patients with DN. In kidney cells, RTN1 overexpression induced ER stress/apoptosis, whereas RTN1 knockdown attenuated tunicamycin-, and hyperglycemia-induced ER stress/apoptosis. Incubation of kidney cells with high glucose media induced RTN1A expression likely through oxidative pathway, while knockdown of RTN1A inhibited high glucose-induced apoptosis. RTN1A interacts with PERK and mutation of its N- or C-terminal domain abolished its effects on ER stress/apoptosis. In vivo, knockdown of Rtn1a expression either before or after kidney injury attenuated renal fibrosis in mice with unilateral ureteral obstruction (UUO) and tubular epithelial cell-specific knockdown of Rtn1a also ameliorated ER stress and renal fibrosis in the UUO mice. Finally, knockdown of Rtn1a also attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ-induced diabetic mice, which were associated with suppression of ER stress markers. Taken together, these data suggest that RTN1 is a mediator of kidney disease progression that exacerbates kidney injury through ER stress and apoptosis. Animal studies: All animal studies were approved by the IACUC committee of Mount Sinai School of Medicine. HIV-1 transgenic mice, Tg26, and their littermates were generated and genotyped as described. Only male heterozygous Tg26 in the FVB/N background were used in the study, because homozygous HIV-transgenic mice are not viable for more than few weeks postnatally. UUO and folic acid-induced nephropathy models were created as described . Mice were grouped as wild type, Tg26 with mild kidney injury, Tg26, with serious kidney injury. The kidneys were collected from these mice for histology, western blot, real-time PCR analysis, and microarray studies. Kidney disease was confirmed by measurement of proteinuria, renal function, and histologic analysis. Microarray studies: Affymetrix gene expression microarrays were performed at the Mount Sinai Institution Microarray Core Facility. The Affymetrix GeneChip® Mouse Genome 430 2.0 Array was used to profile gene expression in the kidney cortex of Tg26 and WT mice 37. One-way analysis of variance test (ANOVA) was applied to the dataset to identify the genes that were differentially expressed between the two groups. P-values were corrected using Benjamini–Hochberg false discovery rate (FDR) with a threshold of 0.05.

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Dehydration impaired normal renal development in infant mice

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