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.

Wound-induced Ca2+wave propagates through a simple release and diffusion mechanism

“…Wounding MCF-10A cells in the presence of apyrase prevents cells from migrating into the wounded area (Figure 3, B and C). This lack of migration in the presence of apyrase agrees with previous wound studies (Wesley et al , 2007; Gault et al , 2014; Nakagawa et al , 2014; Takada et al , 2014). Overall we find that the initial release of ATP is required for Ca 2+ activation, as well as for epithelial wound closure.…”

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

“…46 ATP infusion had a protective effect on renal regeneration after ischemic insult 47 ; however, it may also function as the source of adenosine. 48 In vitro injury studies by Kribben et al 49 and Nakagawa et al 50 identified ATP as a proregenerative factor in isolated rat PT culture.…”

Loss of α(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells

“…Our study focused on the role of α-catenin in regulating cell death since renal tubular epithelium cell death is a hallmark of AKI [23]. Increased apoptosis has been reported in α-catenin deleted mammary glands of mice [24].…”