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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Soc+Nephrol
2015 ; 26
(12
): 3021-34
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
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English Wikipedia
Genetic Background is a Key Determinant of Glomerular Extracellular Matrix
Composition and Organization
#MMPMID25896609
Randles MJ
; Woolf AS
; Huang JL
; Byron A
; Humphries JD
; Price KL
; Kolatsi-Joannou M
; Collinson S
; Denny T
; Knight D
; Mironov A
; Starborg T
; Korstanje R
; Humphries MJ
; Long DA
; Lennon R
J Am Soc Nephrol
2015[Dec]; 26
(12
): 3021-34
PMID25896609
show ga
Glomerular disease often features altered histologic patterns of extracellular
matrix (ECM). Despite this, the potential complexities of the glomerular ECM in
both health and disease are poorly understood. To explore whether genetic
background and sex determine glomerular ECM composition, we investigated two
mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined
with proteomic glomerular ECM analyses. These studies, undertaken in healthy
young adult animals, revealed unique strain- and sex-dependent glomerular ECM
signatures, which correlated with variations in levels of albuminuria and known
predisposition to progressive nephropathy. Among the variation, we observed
changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin
1-?, and meprin 1-?. Differences in protein abundance were validated by
quantitative immunohistochemistry and Western blot analysis, and the collective
differences were not explained by mutations in known ECM or glomerular disease
genes. Within the distinct signatures, we discovered a core set of structural ECM
proteins that form multiple protein-protein interactions and are conserved from
mouse to man. Furthermore, we found striking ultrastructural changes in
glomerular basement membranes in FVB mice. Pathway analysis of merged
transcriptomic and proteomic datasets identified potential ECM regulatory
pathways involving inhibition of matrix metalloproteases, liver X
receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch,
and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer
susceptibility to disease.