Role of fibrillin-1 in hypertensive and diabetic glomerular disease.
The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predisposes individuals to vascular damage in Marfan syndrome, but the role of fibrillin-1 in kidney disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive or diabetic glomerular disease. DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition. To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 mo of life. All DOCA-treated mgR/mgR mice died within 2 wk after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and their wild-type littermates displayed similar blood pressure levels, but albuminuria was significantly lower in mgR/+ than in wild-type mice after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than wild-type mice despite higher blood glucose levels in mgR/mgR and mgR/+ compared with wild-type mice. Blood pressure, blood glucose, and albuminuria did not differ among untreated mgR/mgR, mgR/+, and wild-type mice, respectively. In diabetic mgR/+ and mgR/mgR, but not in wild-type mice, an induction of glomerular decorin expression was observed. Thus underexpression of fibrillin-1 predisposes individuals to lethal aortic dissection in the presence of hypertension. On the other hand, albuminuria as a parameter of microvascular damage in hypertension and diabetes was ameliorated in fibrillin-1-underexpressing mice, possibly due to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease.
Hartner
Andrea
A
Hospital for Children and Adolescents, University of Erlangen-Nurnberg, Erlangen, Germany. andrea.hartner@rzmail.uni-erlangen.de
Schaefer
Liliana
L
Porst
Markus
M
Cordasic
Nada
N
Gabriel
Anke
A
Klanke
Bernd
B
Reinhardt
Dieter P
DP
Hilgers
Karl F
KF
D000419:Albuminuria; D000818:Animals; D058575:Decorin; D003900:Desoxycorticosterone; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006579:Heterozygote; D006720:Homozygote; D006973:Hypertension / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D011509:Proteoglycans / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054392:Adipokines
D058575:Decorin; D003900:Desoxycorticosterone; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D011509:Proteoglycans; C546879:Dcn protein, mouse; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C000605725:Fbn1 protein, rat