Laminin a4-Null Mutant Mice Develop Chronic Kidney Disease with Persistent Overexpression of Platelet-Derived Growth Factor

Laminin-8/9 is synthesized by rat glomerular mesangial cells and is required for PDGF-induced mesangial cell migration. Here the authors show that Lama4-/- mice have progressive glomerular and tubulointerstitial fibrosis. These mice have a significant increase in the expression of platelet-derived growth factor (PDGF)-BB, PDGF-DD, and PDGF receptor beta in association with immature glomerular and peritubular capillaries. In addition, mesangial cell exposure to alpha4-containing laminins results in the down-regulation of PDGF receptor mRNA and protein, suggesting a direct effect of LN411/LN421 on vessel maturation. These data suggest that the failure of laminin alpha4-mediated down-regulation of PDGF activity contributes to the progressive renal lesions in this animal model.