title: Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury.
abstract: Acute kidney injury (AKI) often correlates with poor prognosis and is followed by various severe unfavorable systemic outcomes. It is important to understand the pathophysiology of AKI for the development of novel therapeutic approaches toward promoting renal regeneration after injury. Recent studies have indicated that AKI-induced tubular cell death plays an active role in the onset of tissue regeneration; however, the mechanisms underlying renal tubular repair after injury have yet to be understood. In the present study, we explored molecules that might serve as "danger" signals in mediating tubular regeneration. Kidneys of rats systemically administered the nephrotoxicant cisplatin (to induce AKI) exhibited massive cell proliferation. The proportion of proliferating cells in the total cell distribution was highest in the outer stripe of the outer medulla coincided with where the tubular damage was the most severe in this study. This finding suggests that soluble factors may have been released from damaged cells to stimulate the proliferation of neighboring tubular epithelial cells. In elucidating the mechanism of dying cell-to-surviving cell communication using normal rat kidney NRK-52E epithelial cells, we found a significant increase in ATP levels in supernatants of these cells after the induction of cell death using ultraviolet irradiation. Furthermore, treatment of conditioned supernatants with apyrase or suramin, which inhibits purinergic signaling, resulted in significant decreases in cell proliferation and migration activities. These results demonstrate a novel role for extracellular nucleotides, probably as danger signals in aggravating tubular regeneration after AKI.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan nakashun@kuhp.kyoto-u.ac.jp.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Omura
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin; D004195:Disease Models, Animal; D019394:Ki-67 Antigen / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008297:Male; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects / Q000528:radiation effects
chemical_list: D015415:Biomarkers; D019394:Ki-67 Antigen; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D002945:Cisplatin
keywords: ATP; acute kidney injury; acute renal failure; cell-to-cell communication; compensatory proliferation