Urinary proteome of dogs with kidney injury during babesiosis

Abstract Background Acute kidney injury is the most frequent complication of babesiosis in dogs and may provide a natural model for identifying early and specific markers of kidney injury in this species. There are limited data on urine proteomics in dogs, and none of the effect of babesiosis on the urine proteome. This study aimed to identify urinary proteins of dogs with kidney injury during the natural course of babesiosis caused by Babesia canis, and to compare them with proteins in a control group to reveal any potential biomarkers predicting renal injury before the presence of azotemia. Urine samples were collected from 10 dogs of various breeds and sex with naturally occurring babesiosis, and 10 healthy dogs. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry. Results In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common for both groups. Characteristic analysis of 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses. Conclusions It was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways, and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins, and TGF-β (transforming growth factor β) pathways. Those pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and tyrosine protein kinase Fer, which are potential biomarkers of damage during babesiosis in dogs, that might indicate early renal injury.

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Urinary proteome of dogs with kidney injury during babesiosis

10.21203/rs.2.11052/v3 ◽

2019 ◽

Author(s):

Dagmara Winiarczyk ◽

Katarzyna Michalak ◽

Łukasz Adaszek ◽

Mateusz Winiarczyk ◽

Stanisław Winiarczyk

Keyword(s):

Renal Injury ◽

Metabolic Pathways ◽

Inflammatory Responses ◽

Kidney Injury ◽

Urine Samples ◽

Control Group ◽

Characteristic Analysis ◽

Mesenchymal Transition ◽

Healthy Dogs ◽

Potential Biomarkers

Abstract BackgroundAcute kidney injury is the most frequent complication of babesiosis in dogs and may provide a natural model for identifying early and specific markers of kidney injury in this species. There are limited data on urine proteomics in dogs, and none of the effect of babesiosis on the urine proteome. This study aimed to identify urinary proteins of dogs with kidney injury during the natural course of babesiosis caused by Babesia canis, and to compare them with proteins in a control group to reveal any potential biomarkers predicting renal injury before the presence of azotemia.Urine samples were collected from 10 dogs of various breeds and sex with naturally occurring babesiosis, and 10 healthy dogs. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry. ResultsIn total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common for both groups. Characteristic analysis of 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses. ConclusionsIt was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways, and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins, and TGF-β (transforming growth factor β) pathways. Those pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and tyrosine protein kinase Fer, which are potential biomarkers of damage during babesiosis in dogs, that might indicate early renal injury.

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Urinary proteome of dogs with kidney injury during babesiosis

10.21203/rs.2.11052/v2 ◽

2019 ◽

Author(s):

Dagmara Winiarczyk ◽

Katarzyna Michalak ◽

Łukasz Adaszek ◽

Mateusz Winiarczyk ◽

Stanisław Winiarczyk

Keyword(s):

Metabolic Pathways ◽

Protein Identification ◽

Transforming Growth Factor ◽

Inflammatory Responses ◽

Urine Samples ◽

Control Group ◽

Characteristic Analysis ◽

Mesenchymal Transition ◽

Healthy Dogs ◽

Potential Biomarkers

Abstract This study aimed to identify proteins in the urine of dogs with renal dysfunction during the natural course of babesiosis (n=10) and to compare them with proteins in a control group (n=10) to reveal any potential biomarkers of renal damage. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry. In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common to both groups. Characteristic analysis of the 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses. Furthermore, it was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins and TGF-β (transforming growth factor β) pathways. These pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and FER tyrosine kinase, which are potential biomarkers of damage during babesiosis in dogs that might indicate early renal injury.

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Urinary proteome of dogs with kidney injury during babesiosis

10.21203/rs.2.11052/v1 ◽

2019 ◽

Author(s):

Dagmara Winiarczyk ◽

Katarzyna Michalak ◽

Łukasz Adaszek ◽

Mateusz Winiarczyk ◽

Stanisław Winiarczyk

Keyword(s):

Metabolic Pathways ◽

Protein Identification ◽

Transforming Growth Factor ◽

Inflammatory Responses ◽

Urine Samples ◽

Control Group ◽

Characteristic Analysis ◽

Mesenchymal Transition ◽

Healthy Dogs ◽

Potential Biomarkers

Abstract This study aimed to identify proteins in the urine of dogs with renal dysfunction during the natural course of babesiosis (n=10) and to compare them with proteins in a control group (n=10) to reveal any potential biomarkers of renal damage. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry. In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common to both groups. Characteristic analysis of the 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses. Furthermore, it was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins and TGF-β (transforming growth factor β) pathways. These pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and FER tyrosine kinase, which are potential biomarkers of damage during babesiosis in dogs that might indicate early renal injury.

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Urinary proteome of dogs with kidney injury during babesiosis

10.1101/516120 ◽

2019 ◽

Author(s):

D. Winiarczyk ◽

K. Michalak ◽

L. Adaszek ◽

M. Winiarczyk ◽

J. Madany ◽

...

Keyword(s):

Metabolic Pathways ◽

Transforming Growth Factor ◽

Inflammatory Responses ◽

Urine Samples ◽

Acute Injury ◽

Control Group ◽

2D Electrophoresis ◽

Characteristic Analysis ◽

Mesenchymal Transition ◽

Healthy Dogs

AbstractThis study aimed to identify proteins found in the urine of dogs with renal dysfunction leading to acute injury during the natural course of babesiosis (n=10) and to compare them with proteins of a control group (n=10) to reveal any potential biomarkers of renal damage. Pooled urine samples of both groups were separated by 2D electrophoresis (two dimensional electrophoresis), followed by the identification of all proteins using MALDI-TOF mass spectrometry (matrix assisted laser desorption ionization-time of flight). In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common to both groups. Characteristic analysis of the 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways that were attributed to immune and inflammatory response development. Furthermore, it was hypothesized that the epithelial-mesenchymal transition might play an important role in mechanisms underlying pathological renal tissue changes during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways and 4 of the 8 proteins associated with these pathways. These included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukin and TGF-β (transforming growth factor β) pathways. These pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and FER tyrosine kinase, which are potential damage biomarkers during babesiosis in dogs that might be assigned to early renal injury.

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The p53 inhibitor pifithrin-α can stimulate fibrosis in a rat model of ischemic acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00317.2011 ◽

2012 ◽

Vol 302 (2) ◽

pp. F284-F291 ◽

Cited By ~ 38

Author(s):

Pierre C. Dagher ◽

Erik M. Mai ◽

Takashi Hato ◽

So-Young Lee ◽

Melissa D. Anderson ◽

...

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Responses ◽

Kidney Injury ◽

Vehicle Control ◽

Acute Administration ◽

Protective Effects ◽

Long Term Effects ◽

Mesenchymal Transition ◽

The Impact ◽

Microvascular Rarefaction

Inhibition of the tumor suppressor p53 diminishes tubular cell apoptosis and protects renal function in animal models of acute kidney injury (AKI). Therefore, targeting p53 has become an attractive therapeutic strategy in the approach to AKI. Although the acute protective effects of p53 inhibition in AKI have been examined, there is still relatively little known regarding the impact of acute p53 inhibition on the chronic sequelae of AKI. Consequently, we utilized the p53 inhibitor pifithrin-α to examine the long-term effects of p53 inhibition in a rodent model of ischemic AKI. Male Sprague-Dawley rats were subjected to bilateral renal artery clamping for 30 min followed by reperfusion for up to 8 wk. Pifithrin-α or vehicle control was administered at the time of surgery and then daily for 2 days [brief acute administration (BA)] or 7 days [prolonged acute administration (PA)]. Despite the acute protective effect of pifithrin-α in models of ischemic AKI, we found no protection in the microvascular rarefaction at 4 wk or development fibrosis at 8 wk with pifithrin-α administered on the BA schedule compared with vehicle control-treated animals. Furthermore, pifithrin-α administered on a PA schedule actually produced worse fibrosis compared with vehicle control animals after ischemic injury [21%/area (SD4.4) vs.16%/area (SD3.6)] as well as under sham conditions [2.6%/area (SD1.8) vs. 4.7%/area (SD1.3)]. The development of fibrosis with PA administration was independent of microvascular rarefaction. We identified enhanced extracellular matrix production, epithelial-to-mesenchymal transition, and amplified inflammatory responses as potential contributors to the augmented fibrosis observed with PA administration of pifithrin-α.

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Netrin-1 and kidney injury. II. Netrin-1 is an early biomarker of acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00507.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. F731-F738 ◽

Cited By ~ 78

Author(s):

W. Brian Reeves ◽

Osun Kwon ◽

Ganesan Ramesh

Keyword(s):

Acute Kidney Injury ◽

Folic Acid ◽

Serum Creatinine ◽

Renal Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Peak Level ◽

Urine Samples ◽

Mortality And Morbidity ◽

Early Biomarker

Acute kidney injury is an important complication in hospitalized patients often diagnosed late and associated with high mortality and morbidity. Although biomarkers for nephrotoxicity are available, they often lack sensitivity and specificity for detecting tubular injury. Netrin-1 is a laminin-like molecule highly expressed in many organs including kidney. To determine the value of netrin-1 as a biomarker of renal injury, we analyzed its urinary excretion following ischemia-reperfusion-, cisplatin-, folic acid-, and endotoxin-induced renal injury in mice. Urinary netrin-1 levels increased markedly within 3 h of ischemia-reperfusion (40 ± 14-fold, P < 0.01 vs. baseline), reached a peak level at 6 h, and decreased thereafter, returning to near baseline by 72 h. Serum creatinine significantly increased only after 24 h of reperfusion. Similarly, in cisplatin-, folic acid-, and lipopolysaccharide-treated mice, urine netrin-1 excretion increased as early as 1 h and reached a peak level at 6 h after injection. However, serum creatinine was raised significantly after 6, 24, and 72 h after folic acid, lipopolysaccharide, and cisplatin administration, respectively. NGAL excretion in folic acid- and lipopolysaccharide-treated mice urine samples could only be detected by 24 h after drug administration. Furthermore, urinary netrin-1 excretion increased dramatically in 13 acute renal failure patients, whereas none was detected in 6 healthy volunteer urine samples. Immunohistochemical localization showed that netrin-1 is highly expressed in tubular epithelial cells in transplanted human kidney. We conclude that urinary netrin-1 is a promising early biomarker of renal injury.

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Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

Biomedicines ◽

10.3390/biomedicines8120572 ◽

2020 ◽

Vol 8 (12) ◽

pp. 572

Author(s):

Jung-Yeon Kim ◽

Jungmin Jo ◽

Jaechan Leem ◽

Kwan-Kyu Park

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Renal Injury ◽

Manganese Superoxide Dismutase ◽

Immune Cell ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Kidney Injury ◽

Pleiotropic Effects ◽

Induced Apoptosis ◽

Vascular Adhesion

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

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DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury

Cell Death Discovery ◽

10.1038/s41420-021-00528-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yinwu Bao ◽

Mengqiu Bai ◽

Huanhuan Zhu ◽

Yuan Yuan ◽

Ying Wang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Signaling Pathway ◽

Cell Injury ◽

Inflammatory Responses ◽

Kidney Injury ◽

Renal Tissue ◽

Clinical Samples ◽

Mice Model ◽

Expression Levels ◽

Ppar Signaling

AbstractDemethylase Tet2 plays a vital role in the immune response. Acute kidney injury (AKI) initiation and maintenance phases are marked by inflammatory responses and leukocyte recruitment in endothelial and tubular cell injury processes. However, the role of Tet2 in AKI is poorly defined. Our study determined the degree of renal tissue damage associated with Tet2 gene expression levels in a cisplatin-induced AKI mice model. Tet2-knockout (KO) mice with cisplatin treatment experienced severe tubular necrosis and dilatation, inflammation, and AKI markers’ expression levels than the wild-type mice. In addition, the administration of Tet2 plasmid protected Tet2-KO mice from cisplatin-induced nephrotoxicity, but not Tet2-catalytic-dead mutant. Tet2 KO was associated with a change in metabolic pathways like retinol, arachidonic acid, linolenic acid metabolism, and PPAR signaling pathway in the cisplatin-induced mice model. Tet2 expression is also downregulated in other AKI mice models and clinical samples. Thus, our results indicate that Tet2 has a renal protective effect during AKI by regulating metabolic and inflammatory responses through the PPAR signaling pathway.

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