Regulation of collagen type IV genes is organ-specific: evidence from a canine model of Alport syndrome.
BACKGROUND
Despite advances in knowledge about collagen type IV at the protein level, little is known about expression of its six alpha chains. X-linked Alport syndrome provides a system to study collagen type IV gene expression within a setting of disturbed protein synthesis. Mutations in the alpha5 chain result in loss of the alpha3/alpha4/alpha5 and alpha1/alpha2/alpha5/alpha6 networks from the kidney, with progressive renal disease.


METHODS
We used a canine model of Alport syndrome to measure expression of the six type IV collagen chains from 11 days to 7(1/2) months of age. We determined to what extent message levels in kidney change over time, and what correlation exists with clinical and pathologic changes in glomeruli, and the primary mutation. The latter was evaluated by examining testis, an organ normally containing the same collagen type IV networks but uninvolved by disease.


RESULTS
The alpha1 to alpha6 mRNAs were expressed at all time points in normal canine kidney. By comparison to normal, in Alport dog kidney, the alpha1 and alpha2 mRNAs were up-regulated after 2 months of age, alpha3 and alpha4 mRNAs were down-regulated by 2 months of age, and the alpha5 mRNA was almost undetectable at any time. In testis, all mRNAs were expressed at comparable levels in normal and affected dogs other than the alpha5 chain, which was not expressed in affected testis.


CONCLUSIONS
Normal expression of collagen type IV is under control mechanisms specific to each organ and to individual chains. The altered expression in canine Alport syndrome is not the direct result of the mutation, since these changes do not occur in all organs nor are they present from birth. Instead, collagen type IV expression is influenced by disease, with down-regulation of alpha3 and alpha4 chains temporally related to the onset of proteinuria, and up-regulation of alpha1 and alpha2 chains to glomerulosclerosis. This dysregulation of the alpha3 and alpha4 chains is unique to this Alport model, and suggests an unidentified mechanism linking pathology with down-regulation of expression of these two chains.
Zheng
Keqin
K
Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
Perry
Julie
J
Harvey
Scott J
SJ
Sado
Yoshikazu
Y
Ninomiya
Yoshifumi
Y
Jefferson
Barbara
B
Jacobs
Robert
R
Hudson
Billy G
BG
Thorner
Paul S
PS
D000818:Animals; D015152:Blotting, Northern; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007668:Kidney / Q000502:physiology; D060850:LIM-Homeodomain Proteins; D008297:Male; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000503:physiopathology*; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis; D013737:Testis / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
D024141:Collagen Type IV; D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D012333:RNA, Messenger; D014157:Transcription Factors