Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish

Abstract

Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI), as an enhancer of renal recovery, and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a , enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 (Kim-1) expression, and lowers the number of infiltrating macrophages. Further, we found that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate that the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic. .

Major signaling pathways and key mediators of macrophages in acute kidney injury (Review)

“…Locally synthesized RA inhibits the pro-inflammatory M1 phenotype, thus reducing macrophage-dependent damage and activating RA signaling in the damaged tubular epithelium, which in turn promotes the selective activation of M2 macrophages ( 68 ). It was previously demonstrated that the effect of 4-(phenylthio) butanoic acid (PTBA) on the proliferation of RTECs is dependent on RA signaling ( 69 ). The therapeutic characteristics of PTBA are not limited to the kidney, since PTBA also increases the proliferation of cardiomyocytes and reduces fibrosis after heart injury in adult zebrafish.…”

“…The therapeutic characteristics of PTBA are not limited to the kidney, since PTBA also increases the proliferation of cardiomyocytes and reduces fibrosis after heart injury in adult zebrafish. This provides a critical insight into the mechanism by which PTBA enhances repair in AKI ( 69 ). In addition, it has also been reported that RA has a beneficial effect on CI-AKI in vivo and in vitro .…”

Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

“…Several drugs have been shown to improve kidney regeneration, and, among those, histone deacetylase (HDAC) inhibitors (HDACis) may be a promising therapeutic option for the treatment of AKI [ 97 , 98 , 99 , 100 , 101 , 102 ]. HDACs form a group of enzymes involved in multiple cellular processes by removing the acetyl group from histone or nonhistone proteins [ 103 ].…”

Modeling oxidative injury response in human kidney organoids

“…Using a simple bioreactor-based method for generating human kidney organoids from iPSCs [25,26], we hypothesized hemin-induced ROS-mediated injury and fibrosis could be a valuable tool for evaluating potential therapeutics. Here, we show how this fibrotic model can be used to test the efficacy of promising anti-fibrotic agents such as 4-(phenylthio)butanoic acid (PTBA), which we have previously shown can ameliorate injury and fibrosis in mouse models of AKI [27][28][29][30][31].…”