Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease.
Patients with Alport's syndrome develop a number of pro-inflammatory cytokine and matrix metalloproteinase (MMP) abnormalities that contribute to progressive renal failure. Changes in the composition and structure of the glomerular basement membranes likely alter the biomechanics of cell adhesion and signaling in these patients. To test if enhanced strain on the capillary tuft due to these structural changes contributes to altered gene regulation, we subjected cultured podocytes to cyclic biomechanical strain. There was robust induction of interleukin (IL)-6, along with MMP-3, -9, -10, and -14, but not MMP-2 or -12 by increased strain. Neutralizing antibodies against IL-6 attenuated the strain-mediated induction of MMP-3 and -10. Alport mice treated with a general inhibitor of nitric oxide synthase (L-NAME) developed significant hypertension and increased IL-6 and MMP-3 and -10 in their glomeruli relative to those of normotensive Alport mice. These hypertensive Alport mice also had elevated proteinuria along with more advanced histological and ultrastructural glomerular basement membrane damage. We suggest that MMP and cytokine dysregulation may constitute a maladaptive response to biomechanical strain in the podocytes of Alport patients, thus contributing to glomerular disease initiation and progression.
Meehan
Daniel T
DT
Boys Town National Research Hospital, Omaha, Nebraska 68131, USA.
Delimont
Duane
D
Cheung
Linda
L
Zallocchi
Marisa
M
Sansom
Steven C
SC
Holzclaw
J David
JD
Rao
Velidi
V
Cosgrove
Dominic
D
D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001794:Blood Pressure; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D050533:Glomerular Basement Membrane / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000503:physiopathology; D053506:Matrix Metalloproteinase 10 / Q000235:genetics; D053511:Matrix Metalloproteinase 14 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D013314:Stress, Mechanical; D013997:Time Factors
D015850:Interleukin-6; C507096:Mmp14 protein, mouse; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D053506:Matrix Metalloproteinase 10; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14; D019331:NG-Nitroarginine Methyl Ester