γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia

Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal functions and survival after ischemia/reperfusion injury. Vehicle or GTT (200 mg/kg) were administered to mice 12 h before bilateral kidney ischemia, and endpoints were assessed at different timepoints of reperfusion. GTT treatment reduced decreases in state 3 respiration and accelerated recovery of this function after ischemia. GTT prevented decreases in activities of complexes I and III of the respiratory chain, and blocked ischemia-induced decreases in F0F1-ATPase activity and ATP content in renal cortical tissue. GTT improved renal morphology at 72 h after ischemia, reduced numbers of necrotic proximal tubular and inflammatory cells, and enhanced tubular regeneration. GTT treatment ameliorated increases in plasma creatinine levels and accelerated recovery of creatinine levels after ischemia. Lastly, 89% of mice receiving GTT and 70% of those receiving vehicle survived ischemia. Conclusions: Our data show novel observations that GTT administration improves mitochondrial respiration, prevents ATP deficits, promotes tubular regeneration, ameliorates decreases in renal functions, and increases survival after acute kidney injury in mice.

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A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00222.2015 ◽

2015 ◽

Vol 309 (10) ◽

pp. F852-F863 ◽

Cited By ~ 4

Author(s):

Sara Hirsch ◽

Tarek El-Achkar ◽

Lynn Robbins ◽

Jeannine Basta ◽

Monique Heitmeier ◽

...

Keyword(s):

Acute Kidney Injury ◽

Mouse Model ◽

Congenital Anomalies ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Acute Injury ◽

Null Alleles ◽

Heme Oxygenase 1 ◽

Adult Kidney

It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS ( Sall1 TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1 TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1 TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1 TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1 TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury.

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Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury

Journal of Immunology Research ◽

10.1155/2017/4609502 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Shataakshi Dube ◽

Tejasvi Matam ◽

Jessica Yen ◽

Henry E. Mang ◽

Pierre C. Dagher ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Leukocyte Adhesion ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Organ Injury ◽

Mrna Levels ◽

Kidney Dysfunction ◽

Stat3 Signaling ◽

Proximal Tubular

STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.

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Role of Mitochondrial Therapy for Ischemic-Reperfusion Injury and Acute Kidney Injury

Nephron ◽

10.1159/000520698 ◽

2021 ◽

pp. 1-6

Author(s):

Navjot Pabla ◽

Amandeep Bajwa

Keyword(s):

Acute Kidney Injury ◽

Reperfusion Injury ◽

Mammalian Cells ◽

Immune Cell ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Parenchymal Cell ◽

Kidney Injury ◽

Atp Depletion ◽

Preclinical Models

Acute kidney injury (AKI) is a common clinical disorder associated with decline in renal function because of ischemic and nephrotoxic insults. The pathophysiology of AKI involves multiple cellular mechanisms, such as kidney parenchymal cell (epithelial and endothelial) dysfunction and immune-cell infiltration. Mitochondrial injury which causes ATP depletion and triggers apoptosis and necrosis is at the heart of ischemia reperfusion injury (IRI). Pharmacological (SS-31 or MitoQ), cellular (dendritic cells or mesenchymal stem cells), or genetic strategies that either directly or indirectly preserve mitochondrial integrity and function have been shown to mitigate IRI-linked AKI in preclinical models. Interestingly, isolated mitochondria have been recently shown to be taken up by various mammalian cells resulting in incorporation of transplanted mitochondria into the endogenous mitochondrial network of recipient cells and contributing to protection from ischemic injury in various preclinical models of ischemia including the heart, liver, and kidneys. The mini review summarizes the current available therapeutic strategies that improve kidney function by targeting mitochondria health.

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Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.778569 ◽

2021 ◽

Vol 14 ◽

Author(s):

Nguyen Thanh Nhu ◽

Qing Li ◽

Yijie Liu ◽

Jian Xu ◽

Shu-Yun Xiao ◽

...

Keyword(s):

Systematic Review ◽

Ischemic Stroke ◽

Brain Injury ◽

Mitochondrial Dysfunction ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Atp Depletion ◽

Mitochondrial Functions

This systematic review sought to determine the effects of Mitochondrial division inhibitor-1 (Mdivi-1) on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in ischemia/reperfusion (I/R) injury after ischemic stroke. Pubmed, Web of Science, and EMBASE databases were searched through July 2021. The studies published in English language that mentioned the effects of Mdivi-1 on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in I/R-induced brain injury were included. The CAMARADES checklist (for in vivo studies) and the TOXRTOOL checklist (for in vitro studies) were used for study quality evaluation. Twelve studies were included (median CAMARADES score = 6; TOXRTOOL scores ranging from 16 to 18). All studies investigated neural mitochondrial functions, providing that Mdivi-1 attenuated the mitochondrial membrane potential dissipation, ATP depletion, and complexes I-V abnormalities; enhanced mitochondrial biogenesis, as well as inactivated mitochondrial fission and mitophagy in I/R-induced brain injury. Ten studies analyzed neural mitochondria-mediated apoptosis, showing that Mdivi-1 decreased the levels of mitochondria-mediated proapoptotic factors (AIF, Bax, cytochrome c, caspase-9, and caspase-3) and enhanced the level of antiapoptotic factor (Bcl-2) against I/R-induced brain injury. The findings suggest that Mdivi-1 can protect neural mitochondrial functions, thereby attenuating neural mitochondria-mediated apoptosis in I/R-induced brain injury. Our review supports Mdivi-1 as a potential therapeutic compound to reduce brain damage in ischemic stroke (PROSPERO protocol registration ID: CRD42020205808).Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020205808].

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Epithelial Cell Cycle Behaviour in the Injured Kidney

International Journal of Molecular Sciences ◽

10.3390/ijms19072038 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2038 ◽

Cited By ~ 16

Author(s):

Lies Moonen ◽

Patrick D’Haese ◽

Benjamin Vervaet

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Mitogen Activated Protein Kinase ◽

Cell Cycle Regulators ◽

M Phase ◽

Mitogen Activated Protein ◽

Proximal Tubular

Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been repeatedly demonstrated that dysregulation of the cell cycle can cause injured kidneys to progress to CKD. More precisely, severe AKI causes PTCs to arrest in the G1/S or G2/M phase of the cell cycle, leading to maladaptive repair and a fibrotic outcome. The mechanisms causing these arrests are far from known. The arrest might, at least partially, be attributed to DNA damage since activation of the DNA-damage response pathway leads to cell cycle arrest. Alternatively, cytokine signalling via nuclear factor kappa beta (NF-κβ) and p38-mitogen-activated protein kinase (p38-MAPK) pathways, and reactive oxygen species (ROS) can play a role independent of DNA damage. In addition, only a handful of cell cycle regulators (e.g., p53, p21) have been thoroughly studied during renal repair. Still, why and how PTCs decide to arrest their cell cycle and how this arrest can efficiently be overcome remain open and challenging questions. In this review we will discuss the evidence for cell cycle involvement during AKI and development of CKD together with putative therapeutic approaches.

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MO339KIDNEY DERIVED APOM AND ITS ROLE IN ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab084.0012 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Line Stattau Bisgaard ◽

Pernille M Christensen ◽

Ernst-Martin Füchtbauer ◽

Lars Bo Nielsen ◽

Christina Christoffersen

Keyword(s):

Acute Kidney Injury ◽

Epithelial Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Epithelial Cells ◽

Wild Type ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

Abstract Background and Aims Acute kidney injury is a severe disease with detrimental outcomes. The underlying ethiology is still elusive and besides dialysis, treatment options are poor. Apolipoprotein M (apoM) is mainly expressed in liver and in proximal tubular epithelial cells in the kidney. In plasma, apoM associates with HDL particles via a retained signal peptide. ApoM is a carrier of sphingosine-1-phosphate (S1P), a small bioactive lipid involved in e.g. angiogenesis, lymphocyte trafficking, and vascular barrier function. Recently, it was shown that apoM/S1P protects against development of liver and lung fibrosis. In urine, apoM is normally undetectable in both wild type mice and healthy humans. However, lack of megalin receptors in proximal tubuli induces loss of apoM into the urine. The biological function of kidney-derived apoM is unknown, but it has been hypothesized that apoM might be secreted to the pre-urine to sequester molecules, such as S1P, from secretion. The aim of this study was to unravel the role of apoM in kidney biology and in acute kidney injury. Method A novel kidney specific human apoM transgenic mouse (RPTEC-hapoMTG), was generated by expressing human apoM under the control of the proximal tubular epithelial cell specific Sglt2 promoter. The effect of kidney specific apoM overexpression on acute kidney injury was accessed by inducing either cisplatin or ischemia/reperfusion injury. Further, a stable cell line of HK-2 cells overexpressing hapoM (HK-2hapoM-TG) was generated and the cells were cultured on transwells to assess the secretion of apoM to respectively the apical and basolateral site. Results hapoM was present in plasma from RPTEC-hapoMTG mice (mean 0.18 μM), indicating that kidney-derived apoM can be secreted to plasma. When assessing the secretion of hapoM from proximal tubular epithelial cells in vitro, studies support that apoM can be secreted to both the apical (urine) and basolateral (blood) compartment. No differences in kidney injury markers (plasma urea and creatinine) between RPTEC-hapoMTG and wild type (WT) mice subjected to cisplatin injections, or in kidney injury score determined by histological evaluation was found. Similar, we could not detect any histological difference between RPTEC-hapoMTG and WT mice after ischemia/reperfusion injury, and overexpression of hapoM did not affect kidney gene expression of inflammatory markers (i.e. IL6, MCP-1) compared to WT mice. Conclusion Our study suggests that apoM can be secreted to both the apical and basolateral compartment, supporting a role for apoM in sequestering molecules from secretion in urine. Transgenic overexpression of apoM in proximal tubular epithelial cells of mice did not protect against acute kidney injury.

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Transcriptional modulation of the T helper 17/interleukin 17 axis ameliorates renal ischemia-reperfusion injury

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy370 ◽

2018 ◽

Vol 34 (9) ◽

pp. 1481-1498 ◽

Cited By ~ 10

Author(s):

Jae Wook Lee ◽

Eunjin Bae ◽

Sun-Ho Kwon ◽

Mi-Yeon Yu ◽

Ran-Hui Cha ◽

...

Keyword(s):

T Cell ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Interleukin 17 ◽

T Helper ◽

T Helper 17 ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

Abstract Background Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor critical for T-cell function. Although inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway has been reported to be protective against ischemia-reperfusion injury (IRI), the role of T cell–associated STAT3 in the pathogenesis of renal IRI has not been specifically defined. Methods We induced renal IRI in both mice with T cell–specific STAT3 knockout (Lck-Cre;STAT3flox/flox) and wild-type controls (C57BL/6) and assessed renal damage and inflammation at 48 h after IRI. Human proximal tubular epithelial cells grown under hypoxia were treated with a JAK2 inhibitor, caffeic acid 3,4-dihydroxy-phenylethyl ester, to determine the effect of JAK2/STAT3 inhibition on renal epithelia. Independently, we disrupted Cln 3-requiring 9 (Ctr9) to inhibit T helper 17 (Th17) activation via RNA interference and determined if Ctr9 inhibition aggravates renal injury through upregulated Th17 activation. Results The Lck-Cre;STAT3flox/flox mice exhibited significantly reduced kidney damage compared with controls. This protective effect was associated with reduced intrarenal Th17 infiltration and proinflammatory cytokines. Human proximal tubular epithelial cells under hypoxia exhibited significant upregulation of interleukin 17 receptors, and pharmacologic inhibition of JAK2 significantly ameliorated this change. RNA interference with Ctr9 in splenocytes enhanced differentiation into Th17 cells. In vivo knockdown of Ctr9 in mice with renal IRI further aggravated Th17-associated inflammation and kidney injury. Conclusions STAT3 in T cells contributes to renal IRI through Th17 activation. Inhibition of Ctr9 further enhances Th17 activation and aggravates kidney injury, further supporting the role of Th17 cells in renal IRI.

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Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury

Scientific Reports ◽

10.1038/s41598-020-78936-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Maryam El-Rashid ◽

Danny Nguyen-Ngo ◽

Nikita Minhas ◽

Daniel N. Meijles ◽

Jennifer Li ◽

...

Keyword(s):

Cell Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Drug Repurposing ◽

Acute Injury ◽

Tunel Staining ◽

Effective Measure ◽

Major Health Problem ◽

Chronic Kidney Injury

AbstractAcute kidney injury (AKI) is a major health problem affecting millions of patients globally. There is no effective treatment for AKI and new therapies are urgently needed. Novel drug development, testing and progression to clinical trials is overwhelmingly expensive. Drug repurposing is a more cost-effective measure. We identified 2 commonly used drugs (colchicine and metformin) that alter inflammatory cell function and signalling pathways characteristic of AKI, and tested them in models of acute and chronic kidney injury to assess therapeutic benefit. We assessed the renoprotective effects of colchicine or metformin in C57BL/6 mice challenged with renal ischemia reperfusion injury (IRI), treated before or after injury. All animals underwent analysis of renal function and biomolecular phenotyping at 24 h, 48 h and 4 weeks after injury. Murine renal tubular epithelial cells were studied in response to in vitro mimics of IRI. Pre-emptive treatment with colchicine or metformin protected against AKI, with lower serum creatinine, improved histological changes and decreased TUNEL staining. Pro-inflammatory cytokine profile and multiple markers of oxidative stress were not substantially different between groups. Metformin augmented expression of multiple autophagic proteins which was reversed by the addition of hydroxychloroquine. Colchicine led to an increase in inflammatory cells within the renal parenchyma. Chronic exposure after acute injury to either therapeutic agent in the context of reduced renal mass did not mitigate the development of fibrosis, with colchicine significantly worsening an ischemic phenotype. These data indicate that colchicine and metformin affect acute and chronic kidney injury differently. This has significant implications for potential drug repurposing, as baseline renal disease must be considered when selecting medication.

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