Angiotensin-converting enzyme inhibitors have adverse effects in anti-angiogenesis therapy for hepatocellular carcinoma

Zhang, Su; Cao, Man Qing; Hou, Zeyu; Gu, Xiao; Chen, Yongzi; Chen, Lu; Luo, Yi; Chen, Li Wei; Liu, Dong Ming; Zhou, Hong; Zhu, Keyun; Wang, Zhi Wei; Zhang, Xi Hao; Zhu, Xiao Lin; Cui, Yun; Li, Hui Kai; Guo, Hua; Zhang, Ti

doi:10.1016/j.canlet.2020.12.031

Cited by 12 publications

(22 citation statements)

References 56 publications

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“…There were no gene expression changes in other slit-diaphragm-related proteins in either kidney or glomerular samples. In addition, while VEGFs were not changed at the gene expression levels, both Vegfr-1 and Vegfr-2 mRNA levels were down-regulated in glomeruli, which is consistent with observations in patients taking VEGFR inhibitors [24,26].…”

Section: Discussionsupporting

confidence: 89%

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

Yang

Kowalkowski

Ciurlionis

et al. 2021

IJMS

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Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary β2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.

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Section: Discussionsupporting

confidence: 89%

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

Yang

Kowalkowski

Ciurlionis

et al. 2021

IJMS

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“…For patients treated with TKIs or VEGFA inhibitors, no one developed MCN/FSGlike lesions and TMA at the same time [28], but both lesions were observed in different patients receiving the same treatment regimen [26,28]. Our previous study achieved the same results: both TMA and FSG-like lesions were observed in an apatinib-induced proteinuria mouse model [17]. In normal kidneys, VEGFA is mainly produced by podocytes and binds to VEGFR2 on the surface of endothelial cells [36] to maintain the structure and function of the endothelium.…”

Section: Vegfa/vegfr2 Pathway and Proteinuriasupporting

confidence: 56%

“…Although VEGFA-VEGFR2 inhibitors reduce the levels of VEGFA and VEGFR2 in the kidneys of patients with cancer [17,28], not all patients develop proteinuria. Despite the fact that VEGFA and VEGFR2 are the main drivers of angiogenesis, there are many other pro-angiogenic factors [37,38], some of which have been found to be associated with kidney injury.…”

Section: The Mechanism Underlying Abnormal Endothelial-podocyte Crosstalkmentioning

confidence: 99%

“…Despite the fact that angiotensin II receptor blockade (ARB) effectively reduced proteinuria in various kidney diseases such as diabetic nephropathy, obesity-induced renal disease, and HIV-associated nephropathy [12][13][14][15], and that angiotensin-converting enzyme inhibitors (ACEIs) or ARB are recommended for alleviating proteinuria caused by diabetic nephropathy according to guidelines for treating diabetic nephropathy, in clinical practice, ARB did not effectively alleviate the proteinuria caused by bevacizumab; the patient had persistently elevated proteinuria while taking telmisartan [16]. The administration of ACEIs even compromised the anticancer efficacy of antiangiogenic drugs [17,18]. These facts make proteinuria an urgent problem, and the key to solving this problem is to thoroughly understand the mechanism of proteinuria induced by VEGFA-VEGFR2 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the similar pathological types, TKI-induced nephropathy is quite different from the others. For example, the expression levels of VEGFA and VEGFR2 were significantly increased in early diabetic nephropathy, the inhibition of the VEGFA/VEGFR2 pathway attenuated proteinuria [29], while in patients taking TKIs, the expression levels of VEGFA and VEGFR2 were lower than normal [17,28], which is the opposite of diabetic nephropathy. This indicated that, even with similar pathological changes, the mechanism may be totally different.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Abnormal Crosstalk between Endothelial Cells and Podocytes Mediates Tyrosine Kinase Inhibitor (TKI)-Induced Nephrotoxicity

Zhang

2021

Cells

Self Cite

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Vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2 are the main targets of antiangiogenic therapies, and proteinuria is one of the common adverse events associated with the inhibition of the VEGFA/VEGFR2 pathway. The proteinuric kidney damage induced by VEGFR2 tyrosine kinase inhibitors (TKIs) is characterized by podocyte foot process effacement. TKI therapy promotes the formation of abnormal endothelial‒podocyte crosstalk, which plays a key role in TKI-induced podocyte injury and proteinuric nephropathy. This review article summarizes the underlying mechanism by which the abnormal endothelial‒podocyte crosstalk mediates podocyte injury and discusses the possible molecules and signal pathways involved in abnormal endothelial‒podocyte crosstalk. What is more, we highlight the molecules involved in podocyte injury and determine the essential roles of Rac1 and Cdc42; this provides evidence for exploring the abnormal endothelial‒podocyte crosstalk in TKI-induced nephrotoxicity.

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Role of angiotensin in different malignancies

et al. 2023

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Angiotensin-converting enzyme inhibitors have adverse effects in anti-angiogenesis therapy for hepatocellular carcinoma

Cited by 12 publications

References 56 publications

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

Abnormal Crosstalk between Endothelial Cells and Podocytes Mediates Tyrosine Kinase Inhibitor (TKI)-Induced Nephrotoxicity

Role of angiotensin in different malignancies

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