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Geno-transcriptomic dissection of proteinuria in the uninephrectomized rat uncovers a molecular complexity with sexual dimorphism

Item Type:Article
Title:Geno-transcriptomic dissection of proteinuria in the uninephrectomized rat uncovers a molecular complexity with sexual dimorphism
Creators Name:Yagil, Y. and Hessner, M.J. and Schulz, H. and Gosele, C. and Lebdev, L. and Barkalifa, R. and Sapojnikov, M. and Huebner, N. and Yagil, C.
Abstract:Investigation of proteinuria, which pathophysiology remains incompletely understood, is confounded by differences in the phenotype between males and females. We initiated a sex-specific geno-transcriptomic dissection of proteinuria in uninephrectomized male and female Sabra rats that spontaneously develop focal and segmental glomerulosclerosis, testing the hypothesis that different mechanisms might underlie the pathophysiology of proteinuria between the sexes. In the genomic arm, we scanned the genome of 136 male and 111 female uninephrectomized F2 populations derived from crosses between SBH/y and SBN/y. In males, we identified proteinuria-related quantitative trait loci (QTLs) on RNO2 and 20 and protective QTLs on RNO6 and 9. In females, we detected proteinuria-related QTLs on RNO11, 13 and 20. The only QTL overlap between the sexes was on RNO20. Using consomic strains, we confirmed the functional significance of this QTL in both sexes. In the transcriptomic arm, we searched on a genome wide scale for genes that were differentially expressed in the kidneys of SBH/y and SBN/y with and without uninephrectomy. These studies identified within each sex differentially expressed genes that were of relevance to proteinuria. Integrating genomics with transcriptomics, we identified the differentially expressed genes that mapped within the boundaries of the proteinuria-related QTLs, singling out 24 transcripts in males and 30 in females, only 4 of which (Tubb5, Ubd, Psmb8 and C2) were common to both sexes. Data mining revealed that these transcripts were involved in multiple molecular mechanisms, including immunity, inflammation, apoptosis, matrix deposition and protease activity, with no single molecular pathway predominating in either sex. These results suggest that the pathophysiology of proteinuria is highly complex and that some of the underlying mechanisms are shared between the sexes, while others are sex-specific and may account for the difference in the proteinuric phenotype between males and females.
Keywords:Sabra Rats, Linkage Analysis, DNA miroarrays, Consomics, Candidate Genes, Animals, Rats
Source:Physiological Genomics
Publisher:American Physiological Society
Page Range:301-316
Date:29 November 2010
Official Publication:https://doi.org/10.1152/physiolgenomics.00149.2010
PubMed:View item in PubMed

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