1. Physiol Genomics. 2010 Nov 29;42A(4):301-16. doi:
10.1152/physiolgenomics.00149.2010. Epub 2010 Sep 28.
Geno-transcriptomic dissection of proteinuria in the uninephrectomized rat
uncovers a molecular complexity with sexual dimorphism.
Yagil Y(1), Hessner M, Schulz H, Gosele C, Lebedev L, Barkalifa R, Sapojnikov M,
Hubner N, Yagil C.
Author information:
(1)Laboratory for Molecular Medicine and Israeli Rat Genome Center, Faculty of
Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon,
Israel. labmomed@bgu.ac.il
Investigation of proteinuria, whose 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 genomewide scale for genes that were differentially expressed in kidneys of
SBH/y and SBN/y with and without uninephrectomy. These studies identified within
each sex differentially expressed genes of relevance to proteinuria. Integrating
genomics with transcriptomics, we identified 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 are
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.
PMID: 20876844 [PubMed - indexed for MEDLINE]
PUBMED: 20876844
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