Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease

Alport glomerular disease is associated with dysregulation of pro-inflammatory cytokines and matrix metalloproteinases, promoting progressive glomerulonephritis. Changes in composition and structure of Alport GBM resulting from mutations in type IV collagen genes likely alter cell adhesion and cell signaling. Enhanced biomechanical strain on the capillary tuft, resulting from a thinner and less crosslinked GBM may be a source of insult which contributes to gene dysregulation. To test this we subjected cultured podocytes to cyclic biomechanical strain. We observed robust induction of MMP-3, −9, −10, and −14, but not MMP-2 or MMP-12. IL-6 was induced by biomechanical strain, and neutralizing antibodies against IL-6 attenuated induction of MMP-3 and MMP-10. Alport mice given L-NAME salts, which resulted in a significant rise in systolic blood pressure, showed Induction of MMP-3, MMP-10, and IL-6 in glomeruli relative to normotensive Alport mice. Hypertensive Alport mice also had elevated proteinuria, and more advanced GBM disease histologically and ultrastucturally. Collectively these data suggest MMP and cytokine dysregulation may constitute a maladaptive response to biomechanical strain in Alport podocytes, and that this response may contribute to the mechanism of glomerular disease initiation and progression.