title: The kinase domain of death-associated protein kinase is inhibitory for tubulointerstitial fibrosis in chronic obstructive nephropathy.
abstract: Death-associated protein kinase (DAPK) is a Ca2+/calmodulin-dependent serine/threonine kinase that is thought to mediate apoptosis. We have shown that the kinase domain of DAPK is crucial for the induction of renal tubular cell apoptosis in chronic obstructive uropathy (COU) created by unilateral ureteral ligation. DAPK-mutant mice, generated by deletion of 74 amino acids from the catalytic kinase domain, were used to investigate the role of the DAPK kinase domain in renal fibrosis following COU. Interstitial collagen and alpha-smooth muscle actin (alpha-SMA) expressions in situ were compared between obstructed kidneys in wild-type and mutant mice. As a result, tubulointerstitial fibrosis, as quantified by interstitial collagen expression, was significantly augmented in mutant kidneys compared with wild-type kidneys following COU. Furthermore, deletion of the kinase domain from DAPK significantly increased the appearance of alpha-SMA-positive myofibroblasts in the renal interstitium during COU. Thus, our results suggest that the kinase domain deleted by gene targeting plays a suppressive role for the development of renal fibrosis through inhibition of the tubular epithelial-to-mesenchymal transition in a mouse model of COU.
authors.affiliation: Department of Physiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. kazu59@wakayama-med.ac.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Kishino
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shirasawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tsubota
authors.forename: Kyoko
authors.initials: K
authors.lastname: Owada-Makabe
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueyama
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Masanobu
authors.initials: M
authors.lastname: Maeda
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D005355:Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D014517:Ureteral Obstruction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D000199:Actins; D051017:Apoptosis Regulatory Proteins; D024042:Collagen Type I; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases