scholarly journals Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury

2020 ◽  
Vol 21 (12) ◽  
pp. 4545 ◽  
Author(s):  
Hiromasa Miyake ◽  
Katsuyuki Tanabe ◽  
Satoshi Tanimura ◽  
Yuri Nakashima ◽  
Tomoyo Morioka ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Neutrophil Infiltration ◽  
Endothelial Damage ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Inflammatory Infiltration ◽  
Peritubular Capillaries

Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia–reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) and Vash2 homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration.

Diminished NO generation by injured endothelium and loss of macula densa nNOS may contribute to sustained acute kidney injury after ischemia-reperfusion

2009 ◽  
Vol 296 (1) ◽  
pp. F25-F33 ◽  
Author(s):  
Osun Kwon ◽  
Seok-Min Hong ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Glomerular Filtration ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Endothelial Damage ◽  
Macula Densa ◽  
Renal Vasculature ◽  
Peritubular Capillaries ◽  
Recovery Group ◽  
Neuronal Nos

In postischemic acute kidney injury (AKI) or acute renal failure, a dissipation of glomerular filtration pressure is associated with an altered renal vascular tone and reactivity, as well as a loss of vascular autoregulation. To test the hypothesis that renal nitric oxide (NO) generation reflects endothelial damage in the kidney after ischemia-reperfusion, we quantified the urinary NO levels and identified the site of its generation in postischemic AKI. Subjects were 50 recipients of cadaveric renal allografts: 15 with sustained AKI and 35 with recovering renal function. Urine and blood samples were obtained after transplant, and intraoperative allograft biopsies were performed to examine NO synthases (NOSs) in the kidney. In the sustained AKI group, urinary nitrite and nitrate excretion (in μmol/g urine creatinine) was lower (12.3 ± 1.8 and 10.0 ± 1.4 on postoperative days 0 and 3) than in the recovery group [20.0 ± 3.6 and 35.1 ± 5.3 ( P < 0.005 vs. sustained AKI on days 0 and 3) on postoperative days 0 and 3]. Endothelial NOS expression diminished from the peritubular capillaries of 6 of 7 subjects in the sustained AKI group but from only 6 of 16 subjects in the recovery group. No differences were observed in the inducible NOS staining pattern between the two groups. Neuronal NOS staining was rarely observed in the macula densae of subjects but was prominent in control tissues. These findings suggest that a diminished NO generation by injured endothelium and loss of macula densa neuronal NOS could impair the vasodilatory ability of the renal vasculature and contribute to the reduction in the glomerular filtration rate in postischemic AKI.

scholarly journals Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury

Biology Open ◽  
2021 ◽  
Author(s):  
Taro Miyagawa ◽  
Yasunori Iwata ◽  
Megumi Oshima ◽  
Hisayuki Ogura ◽  
Koichi Sato ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Advanced Glycation End Products ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Advanced Glycation ◽  
Renal Tubular Damage ◽  
Glycation End Products ◽  
End Products ◽  
Renal Tubular

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

scholarly journals P2X7 receptor inhibition protects against ischemic acute kidney injury in mice

2015 ◽  
Vol 308 (6) ◽  
pp. C463-C472 ◽  
Author(s):  
Yanli Yan ◽  
Jianwen Bai ◽  
Xiaoxu Zhou ◽  
Jinhua Tang ◽  
Chunming Jiang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Dysfunction ◽  
P2x7 Receptor ◽  
Renal Tubule ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Protective Effects ◽  
Proinflammatory Response ◽  
Hypertensive Nephropathy

Activation of the purinergic P2X7 receptor (P2X7R) has been associated with the development of experimental nephritis and diabetic and hypertensive nephropathy. However, its role in acute kidney injury (AKI) remains unknown. In this study, we examined the effects of P2X7R inhibition in a murine model of ischemia-reperfusion (I/R)-induced AKI using A438079, a selective inhibitor of P2X7R. At 24 h after I/R, mice developed renal dysfunction and renal tubular damage, which was accompanied by elevated expression of P2X7R. Early administration of A438079 immediately or 6 h after the onset of reperfusion protected against renal dysfunction and attenuated kidney damage whereas delayed administration of A438079 at 24 h after restoration of perfusion had no protective effects. The protective actions of A438079 were associated with inhibition of renal tubule injury and cell death and suppression of renal expression of monocyte chemotactic protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). Moreover, I/R injury led to an increase in phosphorylation (activation) of extracellular signal-regulated kinases 1/2 in the kidney; treatment with A438079 diminished this response. Collectively, these results indicate that early P2X7R inhibition is effective against renal tubule injury and proinflammatory response after I/R injury and suggest that targeting P2X7R may be a promising therapeutic strategy for treatment of AKI.

scholarly journals C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Miyako Tanaka ◽  
Marie Saka-Tanaka ◽  
Kozue Ochi ◽  
Kumiko Fujieda ◽  
Yuki Sugiura ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Free Cholesterol ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Sterile Inflammation ◽  
Renal Tubular Cell ◽  
Renal Tubules ◽  
Underlying Mechanisms

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia–reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death–triggered, sustained inflammation after acute kidney injury.

scholarly journals Targeting acute kidney injury in COVID-19

2020 ◽  
Vol 35 (10) ◽  
pp. 1652-1662 ◽  
Author(s):  
John A Kellum ◽  
J W Olivier van Till ◽  
George Mulligan
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Endothelial Damage ◽  
Acid Oxidation ◽  
Acid Base ◽  
The Impact ◽  
Pathophysiologic Mechanisms

Abstract As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in &gt;21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid–base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia–reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.

scholarly journals Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney

2008 ◽  
Vol 294 (4) ◽  
pp. F739-F747 ◽  
Author(s):  
Weiwei Wang ◽  
W. Brian Reeves ◽  
Ganesan Ramesh
Keyword(s):  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Vascular Endothelial Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Endothelial Cell Activation ◽  
Protein Levels ◽  
Peritubular Capillaries ◽  
The Impact

Endogenous mechanisms exist to limit inflammation. One such molecule is netrin. This study examined the impact of ischemia-reperfusion (I/R) on netrin expression and the role of netrin in preventing renal inflammation and injury. All three isoforms of netrin (1, 3, and 4) are expressed in normal kidney. I/R significantly downregulated netrin-1 and -4 mRNA expression, whereas expression of netrin-3 was moderately upregulated at 24 h of reperfusion. The netrin receptor UNC5B mRNA increased at 3 h and but decreased at later time points. Expression of a second netrin receptor, DCC, was not altered significantly. I/R was associated with dramatic changes in netrin-1 protein abundance and localization. Netrin-1 protein levels increased between 3 and 24 h after reperfusion. Immunolocalization showed an interstitial distribution of netrin-1 in sham-operated kidneys which colocalized with Von Willebrand Factor suggesting the presence of netrin-1 in peritubular capillaries. After I/R, interstitial netrin-1 expression decreased and netrin-1 appeared in tubular epithelial cells. By 72 h after reperfusion, netrin-1 reappeared in the interstitium while tubular epithelial staining decreased significantly. Downregulation of netrin-1 in the interstitium corresponded with increased MCP-1 and IL-6 expression and infiltration of leukocytes into the reperfused kidney. Administration of recombinant netrin-1 significantly improved kidney function (blood urea nitrogen: 161 ± 7 vs. 104 ± 24 mg/dl, creatinine: 1.3 ± 0.07 vs. 0.75 ± 0.16 mg/dl, P < 0.05 at 24 h) and reduced tubular damage and leukocyte infiltration in the outer medulla. These results suggest that downregulation of netrin-1 in vascular endothelial cells may promote endothelial cell activation and infiltration of leukocytes into the kidney thereby enhancing tubular injury.

scholarly journals FGF23 ameliorates ischemia-reperfusion induced acute kidney injury via modulation of endothelial progenitor cells: targeting SDF-1/CXCR4 signaling

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Huang-Ming Chang ◽  
Kang-Yung Peng ◽  
Chieh-Kai Chan ◽  
Chiao-Yin Sun ◽  
Ying-Ying Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Ischemia Reperfusion ◽  
Fibroblast Growth Factor 23 ◽  
Kidney Injury ◽  
In Vitro Assays ◽  
Tubular Damage ◽  
Endothelial Progenitor ◽  
Cxcr4 Signaling

AbstractThe levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

scholarly journals Dual role of protease activated receptor 4 in acute kidney injury: contributing to renal injury and inflammation, while maintaining the renal filtration barrier upon acute renal ischemia reperfusion injury

2019 ◽  
Author(s):  
Marcel. P. B. Jansen ◽  
Nike Claessen ◽  
Per W.B. Larsen ◽  
Loes M. Butter ◽  
Sandrine Florquin ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Migration ◽  
Kidney Injury ◽  
Protease Activated Receptors ◽  
Filtration Barrier ◽  
Peritubular Capillaries ◽  
Acute Renal Ischemia

AbstractIschemia reperfusion (I/R) injury triggers the activation of coagulation and inflammation processes involved in the pathophysiology of acute kidney injury (AKI). Coagulation proteases upregulated upon renal I/R injury activate protease activated receptors (PARs), which form an important molecular link between inflammation and coagulation. PAR4 is the major thrombin receptor on mouse platelets, and the only PAR that is expressed on both human and murine platelets. In addition, PAR4 is expressed on other cells including podocytes. We here sought to determine the contribution of PAR4 in the host response to renal I/R injury. Hence, we subjected PAR4 knockout and wild-type mice to renal I/R injury. PAR4 knockout mice exhibited an increased tolerance to renal tubular necrosis and showed a decreased neutrophil influx in response to renal I/R, independent from platelet PAR4. On the other hand, PAR4 deficiency resulted in albumin cast formation in peritubular capillaries and showed a tendency towards albuminuria. Transmission Electron Microscopy revealed an increase in podocyte foot process effacement. Our findings suggest that PAR4 contributes to renal injury likely through facilitating neutrophil migration, independent from platelet PAR4. In addition, PAR4 fulfils an important function in the maintenance of podocyte integrity following renal I/R insult. Subsequently, loss of PAR4 results in albuminuria.

scholarly journals Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Ratnakar Tiwari ◽  
Pinelopi P. Kapitsinou
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Cell Types ◽  
Endothelial Damage ◽  
Adaptation To Hypoxia ◽  
Low Oxygen

Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation

2014 ◽  
Vol 307 (6) ◽  
pp. F718-F726 ◽  
Author(s):  
Song Rong ◽  
Katja Hueper ◽  
Torsten Kirsch ◽  
Robert Greite ◽  
Christian Klemann ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Neutrophil Infiltration ◽  
Major Surgery ◽  
Severe Renal Failure ◽  
Tnf Α ◽  
Apoptosis And Inflammation ◽  
Deficient Mice

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H2b PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H2d recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI.

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