Biology subjects

Pfister, K. E.

Publications and source records attributed to Pfister, K. E..

4 recordsLinked to original sources

bioRxiv2026

Loss of stromal VEGFR2 protects against ischemic acute kidney injury by preserving the renal microvasculature

Injury to the renal microvasculature, particularly the peritubular capillaries, is a defining feature of ischemic acute kidney injury (AKI). Vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a central regulator of endothelial cell survival, proliferation, migration, and vascular remodeling. Although VEGFR2 has been extensively studied in endothelial cells, accumulating evidence suggests that it is also expressed in non-endothelial cell populations, where it may regulate tissue-specific responses to injury. Here, using publicly available single-cell or single-nucleus RNA sequencing data from human and mouse kidneys, we identified VEGFR2 expression in renal stromal populations. Immunostaining further detected phosphorylated VEGFR2 in the renal stroma of mouse kidneys. To determine the functional role of stromal VEGFR2, we utilized renal stroma-specific Vegfr2 KO mice. Stromal VegfR2 deletion attenuated kidney injury after renal ischemia/reperfusion injury (IRI), as evidenced by reduced tubular injury, preservation of renal blood flow, decreased endothelial oxidative stress, and maintenance of the renal microvasculature. Stromal Vegfr2-deficient kidneys also exhibited increased Angpt1 and Tek levels, enhanced endothelial ERK activation, and preserved endothelial adherent junctions. Taken together, these findings reveal an unexpected role for VEGFR2 in the renal stromal lineage and highlight stromal-endothelial communication as a potential therapeutic target for preserving microvascular integrity after ischemic AKI.

pathology↗

bioRxiv2024

Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury

Proximal tubular epithelial cells (PTECs) are particularly vulnerable to acute kidney injury (AKI). While fatty acids are the preferred energy source for PTECs via fatty acid oxidation (FAO), FAO-mediated H2O2 production in mitochondria has been shown to be a major source of oxidative stress. We have previously shown that a mitochondrial flavoprotein, long-chain acyl-CoA dehydrogenase (LCAD), which catalyzes a key step in mitochondrial FAO, directly produces H2O2 in vitro. Further we have established that loss of a lysine deacylase, Sirtuin 5 (Sirt5-/-), induces hypersuccinylation and inhibition of mitochondrial FAO genes to stimulate peroxisomal FAO and to protect against AKI. However, the role of LCAD has yet to be determined. Mass spectrometry data acquisition revealed that LCAD is hypersuccinylated in Sirt5-/- kidneys after AKI. Following two distinct models of AKI, cisplatin treatment or renal ischemia/reperfusion (IRI), LCAD knockout mice (LCAD-/-) demonstrated renoprotection against AKI. Specifically, LCAD-/- kidneys displayed mitigated renal tubular injury, decreased oxidative stress, preserved mitochondrial function, enhanced peroxisomal FAO, and decreased ferroptotic cell death. LCAD deficiency confers protection against two distinct models of AKI. This suggests a therapeutically attractive mechanism whereby preserved mitochondrial respiration as well as enhanced peroxisomal FAO by loss of LCAD mediates renoprotection against AKI.

pathology↗

bioRxiv2023

Dicarboxylic acid supplementation protects from acute kidney injury via stimulation of renal peroxisomal activity

IntroductionLysine succinylation is a post-translational modification associated with the control of several diseases, including acute kidney injury (AKI). It is suggested that hypersuccinylation favors peroxisomal fatty acid oxidation (FAO) instead of mitochondrial. In addition, the medium-chain fatty acids (MCFAs) dodecanedioic acid (DC12) and octanedioic acid (DC8), upon FAO, generate succinyl-CoA, resulting in hypersuccinylation. DC8 is convenient, inexpensive, easily administered, and efficient. We believe this study could be translated in the future to clinical settings, which would highly benefit patients at high risk of AKI. Methods and ResultsTo test the protective roles of MCFAs during AKI, mice were fed with control, 10% DC12, or 10% DC8 diet, then, subjected to either ischemic-AKI, or cisplatin-AKI models. Supplementation was provided until sacrifice. Biochemical, histologic, genetic, and proteomic analysis were performed, the latter involving a lysine-succinylome-based analysis. Both DC8 and DC12 prevented the rise of AKI markers in mice that underwent renal injury. However, DC8 was even more protective against AKI than DC12. Finally, succinylome analysis evidenced that the kidneys of DC8-fed mice showed an extensive succinylation of peroxisomal activity-related proteins, and a decline in mitochondrial FAO, in comparison to control-fed mice. ConclusionDC8 supplementation drives renal protein hypersuccinylation, promoting a shift from mitochondrial to peroxisomal FAO, and protecting against AKI. Significance StatementLysine succinylation of proteins is shown to control several diseases, including acute kidney injury (AKI). Here we show that mice supplemented with the medium-chain fatty acid octanedioic acid successfully presented a high level of succinylation and were protected from both ischemia-reperfusion- and cisplatin-induced AKI. Moreover, our study demonstrates that peroxisomal activity was increased while mitochondrial activity was preserved, suggesting that the metabolism of diet-obtained medium-chain fatty acids by peroxisomes is renoprotective.

pathology↗

bioRxiv2021

AURKB/Ipl1 restarts replication forks to recover from replication stress.

Aurora kinase B (AURKB in human, Ipl1 in S. cerevisiae) is a master regulator of mitosis and its dysregulation has been implicated in chromosome instability. AURKB accumulates in the nucleus in S-phase and is regulated by CHK1 but has not been implicated in in the DNA Damage Response (DDR). Here we show that AURKB has a conserved role to recover from replication stress and restart replication forks. Active AURKB is localized to replication forks after a prolonged arrest. CHK1 phosphorylation of AURKB induces activating phosphorylation of PLK1 and both Aurora and Plk1 are required to deactivate the DDR. Clinical trials with AURKB inhibitors are designed to target established roles for AURKB in mitosis. Our data suggest combinations of AURKB inhibitors and DNA damaging agents could be of therapeutic importance.

cell biology↗