Kidney Microcirculation as a Target for Innovative Therapies in AKI

Acute kidney injury (AKI) is a serious multifactorial conditions accompanied by the loss of function and damage. The renal microcirculation plays a crucial role in maintaining the kidney’s functional and structural integrity for oxygen and nutrient supply and waste product removal. However, alterations in microcirculation and oxygenation due to renal perfusion defects, hypoxia, renal tubular, and endothelial damage can result in AKI and the loss of renal function regardless of systemic hemodynamic changes. The unique structural organization of the renal microvasculature and the presence of autoregulation make it difficult to understand the mechanisms and the occurrence of AKI following disorders such as septic, hemorrhagic, or cardiogenic shock; ischemia/reperfusion; chronic heart failure; cardiorenal syndrome; and hemodilution. In this review, we describe the organization of microcirculation, autoregulation, and pathophysiological alterations leading to AKI. We then suggest innovative therapies focused on the protection of the renal microcirculation and oxygenation to prevent AKI.

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Characterization of the Oxidative Stress in Renal Ischemia/Reperfusion-Induced Cardiorenal Syndrome Type 3

BioMed Research International ◽

10.1155/2020/1605358 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Wellington Caio-Silva ◽

Danielle da Silva Dias ◽

Carolina Victoria Cruz Junho ◽

Karine Panico ◽

Raquel Silva Neres-Santos ◽

...

Keyword(s):

Nitric Oxide ◽

Cell Damage ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Redox Balance ◽

Renal Ischemia ◽

Cellular Damage ◽

Cellular Mechanisms ◽

Inflammatory Conditions

In kidney disease (KD), several factors released into the bloodstream can induce a series of changes in the heart, leading to a wide variety of clinical situations called cardiorenal syndrome (CRS). Reactive oxygen species (ROS) play an important role in the signaling and progression of systemic inflammatory conditions, as observed in KD. The aim of the present study was to characterize the redox balance in renal ischemia/reperfusion-induced cardiac remodeling. C57BL/6 male mice were subjected to occlusion of the left renal pedicle, unilateral, for 60 min, followed by reperfusion for 8 and 15 days, respectively. The following redox balance components were evaluated: catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (FRAP), NADPH oxidase (NOX), nitric oxide synthase (NOS), hydrogen peroxide (H2O2), and the tissue bioavailability of nitric oxide (NO) such as S-nitrosothiol (RSNO) and nitrite (NO2−). The results indicated a process of renoprotection in both kidneys, indicated by the reduction of cellular damage and some oxidant agents. We also observed an increase in the activity of antioxidant enzymes, such as SOD, and an increase in NO bioavailability. In the heart, we noticed an increase in the activity of NOX and NOS, together with increased cell damage on day 8, followed by a reduction in protein damage on day 15. The present study concludes that the kidneys and heart undergo distinct processes of damage and repair at the analyzed times, since the heart is a secondary target of ischemic kidney injury. These results are important for a better understanding of the cellular mechanisms involved in CRS.

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Neuroprotective and nephroprotective effects of remote postconditioning: Prospects for clinical use

Terapevticheskii arkhiv ◽

10.17116/terarkh2016888121-126 ◽

2016 ◽

Vol 88 (8) ◽

pp. 121-126

Author(s):

L N Maslov ◽

S Yu Tsibulnikov ◽

A V Tsepokina ◽

M V Khutornaya ◽

A G Kutikhin ◽

...

Keyword(s):

Cardiac Surgery ◽

Multicenter Study ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Artery Bypass ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Abdominal Aortic Aneurysm Repair ◽

Multicenter Trial ◽

Remote Postconditioning

The results of experimental and clinical studies strongly suggest that remote ischemic preconditioning (RIP) has no neuroprotective effect during cardiac surgery performed under extracorporeal circulation. Remote preconditioning (RP) has no neuroprotective effect in hemorrhagic stroke. A randomized multicenter study is needed to evaluate the efficiency RIP in patients with ischemic stroke. RP reduces the severity of ischemia/reperfusion kidney injury during transplantation. RIP has been established to prevent contrast-induced nephropathy. There is a need for a multicenter trial to evaluate the efficiency of RIP in patients with abdominal aortic aneurysm repair. Analysis of the presented data indicates that RIP fails to prevent cardiorenal syndrome in infants and children during cardiac surgery. The data available in the literature on the capacity of RIP to provide nephroprotective effect in patients after coronary artery bypass surgery are discordant and indicative of the advisability of a multicenter study.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21124545 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4545 ◽

Cited By ~ 1

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.

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Targeting acute kidney injury in COVID-19

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa231 ◽

2020 ◽

Vol 35 (10) ◽

pp. 1652-1662 ◽

Cited By ~ 3

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 >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.

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

AJP Renal Physiology ◽

10.1152/ajprenal.90531.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. F25-F33 ◽

Cited By ~ 55

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.

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

Nephron ◽

10.1159/000518632 ◽

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.

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MO334ERYTHROPOIETIN-STIMULATED HUMAN ENDOTHELIAL PROGENITOR CELLS AMELIORATE INFLAMMATION AND FIBROSIS VIA INFLAMMASOME IN ISCHEMIA/REPERFUSION-INDUCED ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab084.007 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Ha Nee Jang ◽

Jin Hyun Kim ◽

Seunghye Lee ◽

Sehyun Jung ◽

Se-Ho Chang ◽

...

Keyword(s):

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Tissue Injury ◽

Apoptotic Cell ◽

Human Peripheral Blood ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Endothelial Damage ◽

Endothelial Progenitor ◽

Erythroid Progenitor

Abstract Background and Aims Ischemia/reperfusion-induced AKI (IR-AKI) is a major cause of AKI and progress to chronic kidney disease. But an effective therapeutic intervention for IR-AKI is not established yet. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is significantly upregulated during hypoxia. Endothelial progenitor cells (EPCs) are derived from the bone marrow or tissue-resident cells and play major roles in the maintenance of vascular integrity and the repair of endothelial damage. So, we investigated if EPO-stimulated human EPCs could have the renoprotective effects in an IR-AKI mouse model. Method EPCs originated from human peripheral blood were cultured with EPO (10 IU/mL). Mice were assigned to sham, IR only groups, IR with EPC, and IR with EPO-treated EPC. EPCs (5x105 cells, tail vein) were administered twice at 30 min prior to bilateral renal artery occlusion, and 5 min before reperfusion, with all mice sacrificed 24 h after IR-AKI. Results Both EPCs and EPO-treated EPCs significantly attenuated the renal dysfunction associated with IR-AKI, as well as tissue injury. Apoptotic cell death and oxidative stress were significantly reduced in EPC and EPO-treated EPC mice. Expression of PCNA, ICAM-1, MCP-1 and α-SMA were also significantly reduced in EPC and EPO-treated EPC mice. Furthermore, the expression of NLRP3 and caspase-1 via the activation of NF-κB signaling pathways were significantly reduced in EPC and EPO-treated EPC mice. These results show more effective in EPO-treated EPC than EPC alone and suggest EPO might be involved in the development of EPC. Conclusion This study provides that inflammasome-mediated inflammation and fibrosis might be a potential target of EPC as a treatment for IR-AKI.

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Effects of dexmedetomidine on renal microcirculation in ischemia/reperfusion-induced acute kidney injury in rats

Scientific Reports ◽

10.1038/s41598-021-81288-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Szu-Jen Yang ◽

◽

Chia-Ning Fan ◽

Ming-Jiuh Wang ◽

Shou-Zen Fan ◽

...

Keyword(s):

Acute Kidney Injury ◽

Repeated Measures ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Vessel Density ◽

Organ Injury ◽

Small Vessel ◽

Tissue Oxygen Saturation ◽

Flow Index ◽

Renal Microcirculation

AbstractMicrocirculatory dysfunction plays a crucial role in renal ischemia/reperfusion (IR)-induced injury. Dexmedetomidine was reported to ameliorate IR-induced acute kidney injury. This study investigated the effects of dexmedetomidine on renal microcirculation after IR-induced acute kidney injury in rats. In total, 50 rats were randomly allocated to the following five groups (10 in each group): Sham, Control‒IR, Dex (dexmedetomidine) ‒Sham, Dex‒IR, and IR‒Dex group. The microcirculation parameters included total small vessel density, perfused small vessel density (PSVD), proportion of perfused small vessels, microvascular flow index, and tissue oxygen saturation (StO2) were recorded. The repeated measures analysis showed that PSVD on renal surface was higher in the Dex‒IR group than in the Control‒IR group (3.5 mm/mm2, 95% confidence interval [CI] 0.6 to 6.4 mm/mm2, P = 0.01). At 240 min, StO2 on renal surface was lower in the Control‒IR group than in the Sham group (– 7%, 95% CI − 13 to − 1%, P = 0.021), but StO2 did not differ significantly among the Sham, Dex‒IR, and IR‒Dex groups. Our results showed that pretreatment with dexmedetomidine improved renal microcirculation in rats with IR-induced acute kidney injury. However, the adverse effects of low mean arterial pressure and heart rate might offset the protective effect of dexmedetomidine on organ injury.

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