Role of fibrillin-1 in hypertensive and diabetic glomerular disease.

Abstract

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.

• Authors: Andrea Hartner, Liliana Schaefer, Markus Porst, Nada Cordasic, Anke Gabriel, Bernd Klanke, Dieter P Reinhardt, Karl F Hilgers
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 290 Issue 6 Pg. F1329-36 (Jun 2006) ISSN: 1931-857X [Print] United States
• PMID: 16380460 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dcn protein, mouse
• Decorin
• Extracellular Matrix Proteins
• Fbn1 protein, mouse
• Fbn1 protein, rat
• Fibrillin-1
• Fibrillins
• Microfilament Proteins
• Proteoglycans
• Desoxycorticosterone

Topics

• Albuminuria
• Animals
• Decorin
• Desoxycorticosterone
• Diabetes Mellitus, Experimental (complications)
• Diabetic Nephropathies (etiology, pathology, physiopathology)
• Extracellular Matrix Proteins (analysis)
• Female
• Fibrillin-1
• Fibrillins
• Heterozygote
• Homozygote
• Hypertension (etiology, pathology, physiopathology)
• Kidney Glomerulus (pathology, physiopathology)
• Male
• Mice
• Microfilament Proteins (genetics, physiology)
• Mutation
• Proteoglycans (analysis)
• Rats
• Rats, Sprague-Dawley