Study on cell-specific roles of nudear factor KB in the progression of renal diseases with genetically modified animals

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At first, to generate mice lines in which Cre-recombinase is expressed only in adipocyte and proximal tubules S3 segment, aquaporin promoter region with Cre-recombinase expression vector was used to. We obtained 7 lines of mouse, although, Cre-recombinase activity was observed in a patchy manner in the proximal tubules S1 and S2 segments. We also examined the expression of Cre-recombinase mRNA expression in various organs and tissues. Strong expression was seen in testis and adipose tissue, while significant expression was also seen in various tissues, such as liver, muscle, and intestine. From these results, we abandoned these lines of mouse for our study.On the other hand, we have previously developed conditional transgenic mouse, in which IκBΔN, a dominant-negative form of inhibitory factor of NFκB, is expressed in the presence of Cre-recombinase. We obtained double transgenic mouse of IκBΔN conditional transgenic mouse and podocyte-specific Cre-recombinase expressing mouse. Nephrotoxic serum nephritis was induced in this double transgenic mouse and wild-type mouse. Urinary excretion of protein was significantly lower in double transgenic mouse and crescent formation and glomerular changes were less prominent in double transgenic mouse, too. Double transgenic mouse of IκBΔN conditional transgenic mouse and endothelial-cell-specific Cre-recombinase expressing mouse was not born suggesting that endothelial NFκB activity is required to survive during development.Furthermore, we examined roles of clusterin in renal tubular cell apoptosis and it was suggested that clusterin might facilitate apoptosis.From these results, it is suggested that NFκB activity in podocytes plays important roles in the pathogenesis of nephrotoxic serum nephritis.