LIF-STAT3 on renal tubular regeneration process examined by Cre/loxP system

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The purpose of this study is to clarify how the genes involved in LIF-gp 130-STAT3 signal systems act on renal tubular regeneration by Cre/loxP transgenic mice. We succeeded in generating LoxP-LIF mice which expressed LIF in cells expressing Cre. Crossing LoxP-LIF mice with alfa-MHC-Cre mice generated mice in which LIF is highly expressed in myocardiocytes. In the mice, distribution pattern of sympathetic neurons and parasympathetic neurons turned into heart failure pattern. On the other hand, we tried to generated mice in which Cre expresses specifically in renal tubular cells in S3 segment of proximal tubules. However, AQP7-Cre and GGT2-Cre mice did not show S3 segments specific expression of Cre.We analyzed Gsl5-EGFP mice and Gsl5-HB-EGF mice collaborating with Michiko Sekine at Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science. Gsl5 was shown to be localized in the promoter region of core 2 [beta]-1, 6-N-Acetylglucosaminyl transferase, and was shown to be a cis-regulatory element responsible for proximal S3 tubular cell-specific transcription. Utilizing the Gsl5, we generated transgenic mice in which the human heparin-biding EGF-like growth factor (HB-EGF) is specifically expressed in tubular cells in proximal tubule S3 segment. Mice are resistant to diphtheria toxin (DT) because mice HB-EGF does not bind DT. In contrast, human HB-EGF binds DT at high affinity. In Gsl5-HB-EGF, tubular cells in proximal tubule S3 segment were ablated specifically after administration of DT. Using the mice, we clarified the mechanism of acute renal failure and regeneration of tubular cells.The pathological significance of the tubular epithelial-mesenchymal transition (EMT) in kidney diseases is becoming increasingly recognized. We demonstrated that transcriptional factor Snail is involved in renal tubular EMT and that TGF-beta1 regulates Snail at the transcription and protein degradation levels.