Role of fibrillin-1 in hypertensive glomerulosclerosis in mice

The microfibrillar protein fibrillin-1 is an important component of the vascular wall. Defects in fibrillin-1 predispose to vascular damage in Marfan syndrome but the role of fibrillin-1 in microvascular disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive glomerular disease. Deoxycorticosterone (DOCA)-salt hypertension led to a significant increase in glomerular fibrillin-1 mRNA expression and protein deposition in rats (35.0 4.0% of glomerular area positive for fibrillin-1 versus 16.7 3.3% in controls) and mice. To test the functional role of fibrillin-1, DOCA-salt hypertension was induced in mice with a homozygous 5fold underexpression of fibrillin-1 (R/R), as well as in heterozygous (R/ ) and wildtype ( / ) littermates (n 6 to 9 male mice per genotype). Blood pressure was measured by a tail cuff method, and by direct intraarterial recordings in conscious mice. Animals were followed for 6 weeks. Untreated male R/R mice are known to die from aortic dissection during the first 6 months of life. After induction of DOCA-salt hypertension, all R/R mice died within the next two weeks from internal hemorrhage. DOCA-treated R/ and / displayed similar blood pressure levels but albuminuria was significantly lower in R/ than in / (33.2 10.6 versus 170.4 65.3 g/24h) after DOCA treatment. Glomerular deposition of collagen IV was also significantly ameliorated in R/ , compared with / (22.1 1.9 % of glomerular area in R/ versus 10.9 2.0 % in / ) Blood pressure, albuminuria and glomerular collagen IV did not differ between normotensive R/R, R/ and / , respectively. Thus, underexpression of fibrillin-1 predisposes to lethal aortic dissection in the presence of hypertension. On the other hand, microvascular damage in hypertension was ameliorated by fibrillin-1 underexpression. We conclude that the increased expression of fibrillin-1 may contribute to glomerular damage in hypertensive nephrosclerosis.