The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predispose 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. Deoxycorticosterone (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 5-fold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 months of life. All DOCA-treated mgR/mgR mice died within two weeks after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and wildtype (+/+) littermates displayed similar blood pressure levels but albuminuria was significantly lower in mgR/+ than in +/+ after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than +/+ despite higher blood glucose levels in mgR/mgR and mgR/+ compared to +/+ mice. Blood pressure, blood glucose and albuminuria did not differ between untreated mgR/mgR, mgR/+ and +/+, respectively. In diabetic mgR/+ and mgR/mgR, but not in +/+, an induction of glomerular decorin expression was observed. Thus, underexpression of fibrillin-1 predisposes 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.