title: Omi/HtrA2 protease is associated with tubular cell apoptosis and fibrosis induced by unilateral ureteral obstruction.
abstract: Kidney fibrosis, a typical characteristic of chronic renal disease, is associated with tubular epithelial cell apoptosis. The results of our recent studies have shown that Omi/HtrA2 (Omi), a proapoptotic mitochondrial serine protease, performs a crucial function in renal tubular epithelial apoptotic cell death in animal models of acute kidney injury, including cisplatin toxicity and ischemia-reperfusion insult. However, the role of Omi in tubulointerstitial disease-associated fibrosis in the kidney remains to be clearly defined. We evaluated the potential function and molecular mechanism of Omi in ureteral obstruction-induced kidney epithelial cell apoptosis and fibrosis. The mice were subjected to unilateral ureteral obstruction (UUO) via the ligation of the left ureter near the renal pelvis. UUO increased the protein level of Omi in the cytosolic fraction of the kidney, with a concomitant reduction in the mitochondrial fraction. UUO reduced the X-linked inhibitor of apoptosis protein (XIAP), a substrate of Omi, and pro-caspase-3, whereas it increased cleaved poly(ADP-ribose) polymerase (cleaved PARP) and the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells. When mice were treated with ucf-101, an inhibitor of the proteolytic activity of Omi (6.19 microg/day ip), on a daily basis beginning 2 days before UUO and continuing until the end of the experiment, the Omi inhibitor protected XIAP cleavage after UUO and reduced the increment of PARP cleavage and the numbers of TUNEL-positive cells. Furthermore, the Omi inhibitor significantly attenuated UUO-induced increases in fibrotic characteristics in the kidney, including the atrophy and dilation of tubules, expansion of the interstitium, and increases in the expression of collagens, alpha-smooth muscle actin, and fibronectin. In conclusion, Omi/HtrA2 is associated with apoptotic signaling pathways in tubular epithelial cells activated by unilateral ureteral obstruction, thereby resulting in kidney fibrosis.
authors.affiliation: Department of Anatomy, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Jinu
authors.initials: J
authors.lastname: Kim
authors.forename: Dong Sun
authors.initials: DS
authors.lastname: Kim
authors.forename: Mae Ja
authors.initials: MJ
authors.lastname: Park
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Cho
authors.forename: Antonis S
authors.initials: AS
authors.lastname: Zervos
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Kwon Moo
authors.initials: KM
authors.lastname: Park
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology; D005355:Fibrosis; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013871:Thiones / Q000494:pharmacology; D013997:Time Factors; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D024101:Mitochondrial Proteins; D011480:Protease Inhibitors; D011744:Pyrimidinones; D013871:Thiones; C501517:UCF 101; D051636:X-Linked Inhibitor of Apoptosis Protein; D011065:Poly(ADP-ribose) Polymerases; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3