Angiogenesis Markers and Recovery From Acute Kidney Injury: A Piece of the Puzzle?

Bouchard, Josée; Mehta, Ravindra L.

doi:10.1053/j.ajkd.2019.03.421

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…The recent Translational Research Investigating Biomarker Endpoints for AKI study found that high postoperative plasma levels of VEGF A isoform and placental growth factor were associated with reduced risk for AKI and mortality (14). The present finding of high levels of Wnt-7a could coincide with VEGF effects on angiogenesis and endothelial remodeling, thus biomarkers associated with vascular regeneration could be potential biomarkers of kidney recovery (42). c-Myc is a transcription factor that activates the expression of growth-related genes (43).…”

Section: Discussionmentioning

confidence: 73%

Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients

et al. 2021

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Background: Acute kidney injury requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive chronic kidney disease (CKD) among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. Methods: Serum samples collected on day 8 of randomized renal replacement therapy from 72 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile 1305 proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, while another 34 patients remained on dialysis by day 28. Results: Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis compared to patients who remained on dialysis by day 28. Patients were classified into tertiles based on SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles, were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, gender, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day-8 urine volume, and estimated 60-day mortality risk. Conclusions: These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in AKI-D patients.

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Section: Discussionmentioning

confidence: 73%

Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients

et al. 2021

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“…43 As a result, angiogenesis has since been proposed as a possible determinant of recovery from AKI and its long-term effects. 44 Ltbp4S -knockdown resulted in lower CD31 and CD105 expression on days 1 and 3 post-IRI surgery in the mouse model, whereas addition of LTBP4 resulted in increased angiogenesis in both HUVECs and human aortic endothelial cells. We previously reported a relationship between angiogenesis and LTBP4, as demonstrated by the increase in VEGFR1 and VEGFR2 expression in LTBP4-conditioned media-cultured HUVECs.…”

Section: Discussionmentioning

confidence: 84%

LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts

See

Huang

et al. 2023

Circulation Research

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BACKGROUND: As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI. METHODS: LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed. RESULTS: LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4 -knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells. CONCLUSIONS: Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.

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Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis

Huang

Chen

et al. 2023

Acta Pharmacol Sin

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Angiogenesis Markers and Recovery From Acute Kidney Injury: A Piece of the Puzzle?

Abstract: A cute kidney injury (AKI) occurs in 5% to 42% of patients undergoing cardiac surgery and represents a considerable burden in terms of health outcomes and hospital costs. 1 In this population, severe or prolonged AKI

Cited by 4 publications

References 21 publications

Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients

Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients

LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts

Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis

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