Role of fibrillin-1 in hypertensive and diabetic glomerular disease

• Published in: American journal of physiology. Renal physiology Vol. 290; no. 6; pp. F1329 - F1336
• Main Authors: Hartner, Andrea, Schaefer, Liliana, Porst, Markus, Cordasic, Nada, Gabriel, Anke, Klanke, Bernd, Reinhardt, Dieter P, Hilgers, Karl F
• Format: Journal Article
• Language: English
• Published: United States 01.06.2006
• Subjects: Albuminuria; Animals; Decorin; Desoxycorticosterone; Diabetes Mellitus, Experimental - complications; Diabetic Nephropathies - etiology; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Extracellular Matrix Proteins - analysis; Female; Fibrillin-1; Fibrillins; Heterozygote; Homozygote; Hypertension - etiology; Hypertension - pathology; Hypertension - physiopathology; Kidney Glomerulus - pathology; Kidney Glomerulus - physiopathology; Male; Mice; Microfilament Proteins - genetics; Microfilament Proteins - physiology; Mutation; Proteoglycans - analysis; Rats; Rats, Sprague-Dawley
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00284.2005

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.