Human and Murine Kidneys Show Gender- and Species-Specific Gene Expression Differences in Response to Injury

Han Si,Daniel Glicklich,Erwin Bottinger,Melissa Fazzari,Ramandeep S Banga,Ganesh Kambhampati,Janis Lawrence,Manjunath Ramaiah,James Pullman,Katalin Susztak,David B Thomas,Stuart Greenstein,Antje Gruenwald,Vivian Tellis,Pinelopi Kapitsinou,Pawel Michalak

doi:10.1371/journal.pone.0004802

Han Si, Daniel Glicklich + Show 14 more

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https://doi.org/10.1371/journal.pone.0004802

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Abstract

The incidence of End Stage Renal Disease (ESRD) is approximately 50% higher in men than women. In order to understand the molecular basis of this gender disparity, we examined sex specific gene expression patterns in control and diseased, human and murine kidney samples. Using the Affymetrix platform we performed comprehensive gene expression analysis on 42 microdissected human kidney samples (glomeruli and tubules). We identified 67 genes with gender biased expression in healthy human kidneys and 24 transcripts in diseased male and female human kidneys. Similar analysis performed in mice using male and female control and doxorubicin induced nephrotic syndrome kidneys identified significantly larger number of differentially expressed transcripts. The majority of genes showing gender biased expression either in diseased human and murine kidneys were different from those differentially expressed in healthy kidneys. Only 9 sexually dimorphic transcripts were common to healthy human and murine kidneys and five showed differential regulation in both human and murine diseased kidneys. In humans, sex biased genes showed statistical enrichment only to sex chromosomes while in mice they were enriched to sex chromosomes and various autosomes. Thus we present a comprehensive analysis of gender biased genes in the kidney. We show that sexually dimorphic genes in the kidney show species specific regulation. Our results also indicate that male and female kidneys respond differently to injury. These studies could provide the basis for the development of new treatment strategies for men and women with kidney disease.

Highlights

Chronic kidney disease (CKD) affects about 20 million adults and it is a cause of significant morbidity and mortality in the United States [1,2,3]
We used the Significance Analysis of Microarray data (SAM) [22] with a stringent false discovery rate (FDR) of 0.3% and we identified 1,162 differentially expressed transcripts between male and female kidneys
When we compared 67 sex-biased genes in ‘‘healthy’’ human kidneys with 1162 sexually dimorphic genes in the murine kidney (Figure 3A), we identified 9 transcripts that were differentially regulated in both species

Summary

Introduction

Chronic kidney disease (CKD) affects about 20 million adults and it is a cause of significant morbidity and mortality in the United States [1,2,3]. A large meta-analysis (including 11,345 patients from 68 studies) performed recently indicates that patients with autosomal dominant polycystic kidney disease (PKD), IgA nephropathy, membranous nephropathy, or chronic renal disease of unspecified etiology progress more quickly to ESRD [4]. Animal studies suggest that sex hormones per se, rather than genetically determined structural differences, cause the greater susceptibility of male kidneys to progressive renal injury. The biological effects of sex steroid hormones are classically mediated by nuclear receptors. They either act as ligand-activated transcription factors that bind to specific response elements located on the promoters of target genes, or by tethering to transcription factor complexes that contact DNA at alternative sites [9,10]. Sex steroid hormones can exert rapid nongenomic effects including the activation of the MAP kinase pathways [11,12]

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