Urinary Cyclophilin A as Marker of Tubular Cell Death and Kidney Injury

Abstract

Background: Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. Tubular cell death, including necroptotic cell death, is a key feature of AKI. Cyclophilin A (CypA) is an intracellular protein that has been reported to be released during necroptosis. We have now explored CypA as a potential marker for kidney injury in cultured tubular cells and in clinical settings of ischemia-reperfusion injury (IRI), characterized by limitations of current diagnostic criteria for AKI. Methods: CypA was analyzed in cultured human and murine proximal tubular epithelial cells exposed to chemical hypoxia, hypoxia/reoxygenation (H/R) or other cell death (apoptosis, necroptosis, ferroptosis) inducers. Urinary levels of CypA (uCypA) were analyzed in patients after nephron sparing surgery (NSS) in which the contralateral kidney is not disturbed and kidney grafts with initial function. Results: Intracellular CypA remained unchanged while supernatant CypA increased in parallel to cell death induction. uCypA levels were higher in NSS patients with renal artery clamping (that is, with NSS-IRI) than in no clamping (NSS-no IRI), and in kidney transplantation (KT) recipients (KT-IRI) even in the presence of preserved or improving kidney function, while this was not the case for urinary Neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, higher uCypA levels in NSS patients were associated with longer surgery duration and the incidence of AKI increased from 10% when using serum creatinine (sCr) or urinary output criteria to 36% when using high uCypA levels in NNS clamping patients. Conclusions: CypA is released by kidney tubular cells during different forms of cell death, and uCypA increased during IRI-induced clinical kidney injury independently from kidney function parameters. Thus, uCypA is a potential biomarker of kidney injury, which is independent from decreased kidney function.

Construction of a Novel Prognostic Signature in Lung Adenocarcinoma Based on Necroptosis-Related lncRNAs

“…It also suggests a potential pivotal role in tumorigenesis and progression of NSCLC (Furukawa et al, 2005). Peptidylprolyl isomerase A (PPIA), associated with AP001453.2, is an intracellular protein released early in the process of necroptosis and has been identified to be a biomarker for this form of cell death (Cabello et al, 2021). Sirtuin 3 (SIRT3), which is related to AC236972.3, can inhibit the proliferation of human small-cell lung cancer cells by promoting apoptosis and necroptosis (Tang X. et al, 2020).…”

Current update on theranostic roles of cyclophilin A in kidney diseases

“…The increase of eCyPA secreted from human proximal tubular epithelial cells (PTECs) is found after the cells are exposed to harmful agents 62 . PTECs also secrete greater amount of eCyPA during cell death and/or kidney injury 63 .…”

“…eCyPA is secreted from the damaged cells to the extracellular environment 63 . Moreover, circulating eCyPA can filter freely through the glomerulus in the nephron .…”

“…Moreover, circulating eCyPA can filter freely through the glomerulus in the nephron . Therefore, a high level of uCyPA may reflect elevation of eCyPA secretion from the toxic renal cells and/or its increased glomerular filtration or leakage 63 , 66 . The increase of uCyPA in ischemia/reperfusion-induced AKI can thus serve as the biomarker independent from other functional and clinical parameters 63 , 66 .…”

“…Therefore, a high level of uCyPA may reflect elevation of eCyPA secretion from the toxic renal cells and/or its increased glomerular filtration or leakage 63 , 66 . The increase of uCyPA in ischemia/reperfusion-induced AKI can thus serve as the biomarker independent from other functional and clinical parameters 63 , 66 . Also, it is evident that uCyPA may be used in complement with serum creatinine and other classical markers for AKI, e.g., neutrophil gelatinase - associated lipocalin (NGAL).…”