TENASCIN-C PROMOTES HEALING OF HABU-SNAKE VENOM-INDUCED GLOMERULONEPHRITIS - STUDIES IN KNOCKOUT CONGENIC MICE AND IN CULTURE

Mice without the gene for tenascin-C, a multifunctional extracellular matrix protein expressed in many important biological events, includin g around healing, did not show any phenotype. However, it is now obvio us that the phenotype of deletion of one gene frequently depends on th e genetic background. Therefore, we have newly generated tenascin-C kn ockout mice (KO) by backcrossing original KO into three congenic lines : C57BL/6N, BALB/cA, and GRS/A (GR), And we investigated the disease c ourse of reversible kidney injury, Habu-snake venom-induced proliferat ive glomerulonephritis. In all strains, the disease was more severe in KO, but the severity varied With the strain. The KO-GR showed irrever sibility; all treated KO-GR died by the 4th month due to renal failure . The diseased KO-GR showed abnormal regenerative reactions, including reduced proliferation of mesangial cells, key players in glomerulonep hritis, and reduced production of some kinds of cytokines and matrices , leading to poor formation of granulation tissue. In culture, the mes angial cells from the KO-GR had the same potential for proliferation a nd response to cytokines as controls, but interestingly, to achieve th is potential, they required contact with tenascin-C, These reactions w ere blocked by an anti-tenascin monoclonal antibody. The results of th e present study, the first report showing the most dramatic phenotype so far discovered, have strongly suggested the importance of tenascin- C in the resolution of the renal inflammation and that of the genetic background on which the KO was developed.