Lack of nidogen-2 increases blood pressure, glomerular and tubulointerstitial damage in DOCA-salt hypertension.
BACKGROUND
Nidogen-2, an extracellular matrix protein, is ubiquitous in renal basement membranes linking the laminin and collagen IV networks. Nidogen-2-deficient (nidogen-2(-/-)) mice do not exhibit a phenotype, and renal basement membranes appear normal. The functional role of nidogen-2 in the adult kidney under pathological conditions however remains unclear. We tested the hypothesis that nidogen-2 mediated cell-matrix interactions are important to maintain glomerular integrity and structure in renal hyperperfusion and hypertension.


METHODS
Two weeks after unilateral nephrectomy (UNX), desoxycorticosterone (DOCA)-salt hypertension was induced in nidogen-2(-/-) mice and their wild type littermates for 6 weeks. Renal damage was assessed by means of semiquantitative scoring, morphometric analysis, immunohistochemistry and measurement of serum creatinine and albumin excretion.


RESULTS
UNX alone resulted in a very mild increase in renal damage in nidogen-2(-/-) mice compared to wild type animals. Following DOCA-salt treatment, blood pressure, serum creatinine and albumin excretion were significantly higher in nidogen-2(-/-) than in wild type mice. In addition, nidogen-2(-/-) mice showed increased mesangial cell hyperplasia and matrix expansion with higher expression of fibronectin and its receptor alpha8 integrin. Glomerular capillaries were significantly reduced in size and number.


CONCLUSIONS
We demonstrate that in both mild and severe glomerular damage, lack of nidogen-2 is associated with: (i) increased mesangioproliferation; (ii) higher mesangial matrix expansion; and (iii) reduction in glomerular capillary supply. These findings suggest a critical role for nidogen-2 in the maintenance of glomerular structure in the diseased kidney.
Amann
K
K
University of Erlangen-Nuernberg, University of Luebeck, Erlangen, Germany. kerstin.amann@uk-erlangen.de
Haas
C S
CS
Zeiler
G A
GA
Benz
K
K
Bader
B L
BL
Hartner
A
A
Hilgers
K F
KF
D000419:Albuminuria / Q000652:urine; D000818:Animals; D001794:Blood Pressure; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D003404:Creatinine / Q000097:blood; D003900:Desoxycorticosterone / Q000494:pharmacology; D050533:Glomerular Basement Membrane / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D008901:Mineralocorticoids / Q000494:pharmacology; D009392:Nephrectomy
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D008901:Mineralocorticoids; C112846:Nid2 protein, mouse; D003900:Desoxycorticosterone; D003404:Creatinine