Identification of a common molecular pathway in hypertensive renal damage: comparison of rat and human gene expression profiles.
BACKGROUND
There is a common structural progression in hypertensive renal damage with early arterial damage and fibrosis in the juxtamedullary cortex.


METHODS
The present investigation identifies a common pathway using three-gene expression profiles from hypertensive rat models: 60-week-old spontaneously hypertensive rat (SHR), salt-loaded stroke-prone SHR (SHRSP), and the non-clipped kidney after 24 weeks of two-kidney, one-clip hypertension (2K1C). Kidney damage was scored using a specialized system. Gene-expression profiles were determined using microarrays and validated using a panel of 47 genes by quantitative real-time PCR.


RESULTS
All groups showed kidney damage (SHRs: 0.32 ± 0.09 vs. Wistar-Kyoto rats: 0.06 ± 0.03; 2K1C: 0.27 ± 0.13 vs. pooled controls: 0.01 ± 0.01; SHRSP: 1.13 ± 0.14 vs. WKY: 0.04 ± 0.03; all P < 0.05). A total of 1614 genes were changed in the SHR experiment, 1323 in the SHRSP, and 576 in the 2K1C. Eighty-eight genes were similarly regulated in all three models. Gene ontology enrichment analysis identified 59 ontologies that were enriched in all three datasets. These included over-representation to extracellular matrix, response to oxidative stress, and immune system processes. Out of the 88 in-common genes, 40 could be connected in a common pathway that was compared to two gene-expression profiles from human kidneys with histologically verified fibrosis to identify a highly significant number of in-common genes that were also represented in the common genetic pathway.


CONCLUSIONS
There is a common pathway during the development of hypertensive kidney damage in rats irrespective of model. Interestingly, large parts of this common pathway are conserved in human kidney damage, which may indicate a broader importance in the development of chronic kidney disease.
aRenal Research Group, Department of Clinical Medicine bDepartment of Biomedicine, University of Bergen cDepartment of Pathology, Haukeland University Hospital, Bergen, Norway dInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK eDepartment of Medicine, Haukeland University Hospital, Bergen, Norway fIntegrative Physiology, Department of Medical Cell Biology gAnaesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden *Deceased. †Martin W. McBride and Michael Hultström are co-senior authors.
Trude
T
Skogstrand
Sabine
S
Leh
John
J
McClure
Mohammed
M
Dashti
Bjarne M
BM
Iversen
Delyth
D
Graham
Martin W
MW
McBride
Michael
M
Hultström
D000818:Animals; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D059467:Transcriptome
D017673:Sodium Chloride, Dietary