VEGFR3 tyrosine kinase inhibition aggravates cisplatin nephrotoxicity

2021 ◽  
Author(s):  
Laurence M Black ◽  
Elisa R Farrell ◽  
Daria Barwinska ◽  
Gunars Osis ◽  
Anna A Zmijewska ◽  
...  
Keyword(s):  
De Novo ◽  
Kidney Diseases ◽  
Apoptotic Cell ◽  
Three Dimensional ◽  
Kidney Injury ◽  
Protective Role ◽  
Cisplatin Nephrotoxicity ◽  
Novel Approach ◽  
Vascular Congestion ◽  
Renal Vascular

Expansion of renal lymphatic networks, or lymphangiogenesis (LA) is well-recognized during development, and is now being implicated in kidney diseases. Though LA is associated with multiple pathological conditions, very little is known about its role in acute kidney injury (AKI). The purpose of this study was to evaluate the role of LA in a model of cisplatin-induced nephrotoxicity. LA is predominately regulated by VEGF-C and VEGF-D, ligands that exert their function through their cognate receptor VEGFR3. We demonstrate the use of MAZ51, a selective VEGFR3 inhibitor, which caused significantly worse structural and functional kidney damage in cisplatin nephrotoxicity. Apoptotic cell death and inflammation were also increased in the MAZ51 treated animals compared to vehicle-treated animals following cisplatin administration. Notably, MAZ51 caused significant upregulation of intrarenal phospho-NF-kB, phospho-JNK, and IL-6. Cisplatin nephrotoxicity is associated with vascular congestion due to endothelial dysfunction. Using three-dimensional tissue cytometry, a novel approach to explore lymphatics in the kidney, we detected significant vascular autofluorescence attributed to erythrocytes in cisplatin alone treated animals. Interestingly, no such congestion was detected in MAZ51 treated animals. We found increased renal vascular damage in MAZ51 treated animals, whereby MAZ51 caused a modest decrease in endothelial markers Emcn and vWF, with a modest increase in VEGFR2. Our findings identify a protective role for de novo LA in cisplatin nephrotoxicity and provide a rationale for the development of therapeutic approaches targeting LA. Our studies also suggest off target effects of MAZ51 on the vasculature in the setting of cisplatin nephrotoxicity.

scholarly journals CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7642
Author(s):  
Zoran V. Popovic ◽  
Felix Bestvater ◽  
Damir Krunic ◽  
Bernhard K. Krämer ◽  
Raoul Bergner ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Membranous Glomerulonephritis ◽  
Human Kidney ◽  
Protective Role ◽  
Control Group ◽  
Podocyte Injury ◽  
Ccr2 Expression ◽  
Cd73 Expression

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.

scholarly journals The role of heat shock proteins in kidney disease

2016 ◽  
Vol 4 (3) ◽  
pp. 114-117 ◽  
Author(s):  
Shobhana Nayak Rao
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Neurodegenerative Disorders ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Protective Role ◽  
The Family ◽  
Intracellular Proteins ◽  
Shock Proteins

AbstractHeat Shock Proteins (HSP) belong to the family of intracellular proteins that are constitutively expressed and are upregulated by various stressors including heat, oxidative and chemical stress. HSP helps in reparative processes, including the refolding of damaged proteins and the removal of irreparably damaged proteins that would initiate cellular death or apoptosis. A growing body of evidence has expanded the role of HSP and defined their role in diseases such as neurodegenerative disorders, cancer, ischemic heart disease and kidney diseases. The protective role of HSP in ischemic renal injury has been described and HSP impairment has been noted in other forms of kidney injuries including post-transplant situation. Further research into the role of HSP in prevention of kidney injury is crucial if translation from the laboratory to patient bedside has to occur. This article aims to be a review of heat shock protein, and its relevance to kidney diseases.

scholarly journals Kidney-Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Inflammation, Oxidative Stress, and Cisplatin-Induced Nephrotoxicity

2021 ◽  
Vol 22 (6) ◽  
pp. 2793
Author(s):  
John D. Imig ◽  
Md Abdul Hye Khan ◽  
Anna Burkhan ◽  
Guan Chen ◽  
Adeniyi Michael Adebesin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Targeted Delivery ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Thiobarbituric Acid ◽  
Epoxyeicosatrienoic Acid ◽  
Lower Effective Dose ◽  
Cisplatin Nephrotoxicity ◽  
Kidney Injury Molecule 1

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-β-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

scholarly journals A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mi Liu ◽  
Zhanjun Jia ◽  
Ying Sun ◽  
Aihua Zhang ◽  
Tianxin Yang
Keyword(s):  
Oxidative Stress ◽  
Renal Dysfunction ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Apoptotic Response ◽  
Cisplatin Nephrotoxicity ◽  
Histological Damage ◽  
Structural Injury ◽  
Elevated Blood Urea Nitrogen

Accumulating evidence demonstrated that hydrogen sulfide (H2S) is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN) and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1βin circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS) and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

scholarly journals zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function

2012 ◽  
Vol 303 (8) ◽  
pp. F1239-F1250 ◽  
Author(s):  
Christian Herzog ◽  
Cheng Yang ◽  
Alexandrea Holmes ◽  
Gur P. Kaushal
Keyword(s):  
Renal Function ◽  
Therapeutic Agent ◽  
Kidney Injury ◽  
Protective Role ◽  
Autophagic Flux ◽  
Tubular Epithelial Cells ◽  
Cisplatin Nephrotoxicity ◽  
Autophagy Pathway ◽  
Renal Tubular

Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.

scholarly journals Galectin 3 inhibition attenuates renal injury progression in cisplatin-induced nephrotoxicity

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Hong-yan Li ◽  
Shen Yang ◽  
Jing-chun Li ◽  
Jian-xun Feng
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Treatment Options ◽  
Kidney Injury ◽  
Protective Role ◽  
Hek293 Cells ◽  
Kidney Fibrosis ◽  
Galectin 3 ◽  
Injury Progression

Nephrotoxicity is a major toxic effect in chemotherapy, which constitutes up to 60% of hospitalized acute kidney injury (AKI). Very few treatment options exist to slow the transition from AKI to subsequent chronic kidney diseases (CKD). Here, we demonstrate that galectin-3 (Gal-3), a β-galactoside binding lectin that plays an important role in kidney fibrosis and renal failure, is one of the key factors for renal injury progression. Ectopic overexpression of Gal-3 significantly decreased the viability of HEK293, simultaneously inducing of cell cycle arrest and apoptosis. However, inhibition of Gal-3, mediated by modified citrus pectin (MCP), predominantly antagonized the pro-apoptotic effects. Mice were pre-treated with normal or 1% MCP-supplemented drinking water 1 week before cisplatin injection. Analyses of serum creatinine and renal tissue damage indicated that MCP-treated mice demonstrated increased renal function and attenuated renal fibrosis after cisplatin-induced injury. MCP-treated mice also demonstrated decreased renal fibrosis and apoptosis, as revealed by masson trichrome staining and Western blot analysis of cleaved caspase-3. Additionally, the protective role of Gal-3 inhibition in the kidney injury was shown to be mediated by protein kinase C α (PKC-α), which promoted cell apoptosis and collagen I synthesis in HEK293 cells. These results demonstrated the potential Gal-3 and PKC-α as therapeutic targets for the treatment of AKI and CKD.

scholarly journals Cisplatin nephrotoxicity is induced via poly(ADP-ribose) polymerase activation in adult zebrafish and mice

2020 ◽  
Vol 318 (5) ◽  
pp. R843-R854 ◽  
Author(s):  
Myoung-Jin Kim ◽  
Daeun Moon ◽  
Sumi Jung ◽  
Jehee Lee ◽  
Jinu Kim
Keyword(s):  
Acute Kidney Injury ◽  
Genetic Manipulation ◽  
Kidney Diseases ◽  
Parp Inhibitor ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Adult Zebrafish ◽  
Cisplatin Nephrotoxicity ◽  
Alkaline Phosphatase Staining ◽  
Proximal Tubular

Cisplatin is a well-known chemotherapy medication used to treat numerous cancers. However, treatment with cisplatin in cancer therapy has major side effects, such as nephrotoxic acute kidney injury. Adult vertebrate kidneys are commonly used as models of cisplatin-induced nephrotoxic acute kidney injury. Embryonic zebrafish kidney is more simplified and is composed simply of two nephrons and thus is an excellent model for the investigation of cisplatin nephrotoxicity. Here, we developed a novel model to induce cisplatin nephrotoxicity in adult zebrafish and demonstrated that intraperitoneal injection of cisplatin caused a decline in kidney proximal tubular function based on fluorescein-labeled dextran uptake and alkaline phosphatase staining. We also showed that cisplatin induced histological injury of the kidney tubules, quantified by tubular injury scores on the periodic acid-Schiff-stained kidney sections. As shown in a mouse model of cisplatin-induced nephrotoxicity, the activation of poly(ADP-ribose) polymerase (PARP), an enzyme implicated in cisplatin-induced cell death, was markedly increased after cisplatin injection in adult zebrafish. Furthermore, pharmacological inhibition of PARP using a specific PARP inhibitor PJ 34 hydrochloride (PJ34) or 3-aminobenzamide ameliorated kidney proximal tubular functional and histological damages in cisplatin-injected adult zebrafish kidneys. Administration of a combination of PARP inhibitors PJ34 and 3-aminobenzamide additively protected renal function and histology in zebrafish and mouse models of cisplatin nephrotoxicity. In conclusion, these data suggest that adult zebrafish are not only suitable for drug screening and genetic manipulation but also useful as a simplified but powerful model to study the pathophysiology of cisplatin nephrotoxicity and establish new therapies for treating human kidney diseases.

A Plug-and-Play Approach for the De Novo Generation of Dually Functionalised Bispecifics

2019 ◽  
Author(s):  
Antoine Maruani ◽  
Peter A. Szijj ◽  
Calise Bahou ◽  
João C. F. Nogueira ◽  
Stephen Caddick ◽  
...  
Keyword(s):  
De Novo ◽  
Therapeutic Index ◽  
Antibody Fragments ◽  
Bispecific Antibodies ◽  
Full Potential ◽  
Mechanisms Of Resistance ◽  
Large Excess ◽  
Chemical Methods ◽  
New Class ◽  
Novel Approach

<p>Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics in clinical trials and on the market interact with only one target thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics emerged: bispecific antibodies.</p><p>Bispecific formation using chemical methods is rare and low yielding and/or requires a large excess of one of the two proteins to avoid homodimerisation. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalisation of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalised bispecifics with controlled loading in a modular and convergent manner.</p>

Sign in / Sign up

Export Citation Format

Share Document