Response to comment on “Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI”

Renal ischemia-reperfusion (Renal I/R) leads to acute kidney injury (AKI),a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models,both in vitro and in vivo,have been used to study the pathogenic mechanisms of ischemic AKI and to test reno-protective strategies. Aim: To study potential protective effects of artesunate on renal I/R injury. Renal I/R injury was unilaterally induced in adult (3 to 5 months) male Sprague-Dawely rats,whose weights ranged from 180 to 390 g. Thereafter,the animals were pre-treated with artesunate intra-peritoneally,and at the end of reperfusion sacrificed humanely. Plasma,serum and tissue samples were obtained for analysis. Plasma concentrations of NGAL (neutrophil gelatinase associated lipocalin),an iron-trafficking protein involved in multiple processes such as apoptosis,innate immunity and renal development,and tissue concentrations of IL-18 (Interleukin-18) were measured via ELISA analysis. Serum urea and creatinine were also measured in the samples. Artesunate improved renal ischemia reperfusion,including renal function and brought about reductions in inflammatory mediators and kidney tissue injury. Plasma concentrations of NGAL and tissue concentrations of IL-18 were significantly (p < 0.05) lower in the artesunatepretreated group than in the vehicle and control groups. Furthermore,serum concentrations of urea and creatinine were significantly (p < 0.05) decreased in the pretreated group as compared to the control group. Artesunate can significantly improve renal function following I/R through down-regulation of inflammatory parameters and NGAL expression. Furthermore,it could serve as a potential therapy in ischemia reperfusion-induced acute kidney injury.

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MO468NEW URINARY BIOMARKERS DETECT SUBCLINICAL RENAL DAMAGE AFTER SEVERAL ACUTE KIDNEY INJURY EPISODES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab090.0030 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Giampiero A Massaro ◽

Joana Mercado-Hernandez ◽

Ana Carbajo-Uña ◽

Isabel Fuentes-Calvo ◽

Sandra M Sancho Martinez ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Ischemia Reperfusion ◽

Left Kidney ◽

Kidney Injury ◽

Renal Ischemia ◽

Urinary Biomarkers ◽

Control Group ◽

Clinical Parameters ◽

Group 5

Abstract Background and Aims Acute kidney injury (AKI) represents a clinical problem due to its increasing prevalence and association with further morbidities. Observational studies have shown that AKI increases the risk of a new AKI episode, chronic kidney disease (CKD), CKD progression, end-stage renal disease (ESRD), and mortality. Serum creatinine (sCr) is the parameter most used by clinicians for determining AKI and the subsequent recovery, however its use presents several limitations. sCr lacks sensitivity for AKI and provides minimal insight into the renal structure. Indeed, increases in sCr are observed only when glomerular filtration rate decreases more than 50%. Therefore, new markers need to be identified to predict recovery after AKI and to detect residual structural alterations that can cause progression to CKD. We hypothesised that after AKI, there are renal structural abnormalities that cannot be detected by common clinical parameters but may be detected by urinary biomarkers. Method We used 4 weeks old male Wistar rats. Animals were divided into 5 experimental groups: Control group: SHAM operated rats, saline solution i.p.; “CDDP5-SHAM” group: 5 mg/kg cisplatin i.p.; “Ctrl-I/R60” group: 60-minute renal ischemia reperfusion in the left kidney; “CDDP5-I/R60” group: 5 mg/kg cisplatin i.p. and after renal function normalization, 60-minute ischemia-reperfusion (I/R60); “5/6 NEF” group: 5/6 nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and every week thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Urinary biomarkers were analyzed at day 20 (12 days after the second damage and 20 after the first one) by western blot and ELISA. Animals were sacrificed at the same time point in which urinary biomarkers were determined, and renal tissue samples were stained with Masson´s trichrome, Sirius Red and Periodic Acid-Schiff for histological analysis. Results Frequency of AKI episodes is related to the amount and degree of subclinical alterations detected in the kidneys, even though renal filtration is apparently normal. We characterized a novel panel of urinary biomarkers (bk1-bk4) several days after the last insult (day 20) when renal function appeared normal; these biomarkers were present in highest concentrations in the CDDP5-I/R60 experimental group. Conclusion These results demonstrate the importance of the clinical implementation of biomarkers as useful tools for medical support and underline the limitations of the clinical parameters (e.g. sCr, estimated GFR) currently used for renal function assessment. The frequency of AKI episodes is related to a poor prognosis, so a follow up is necessary after AKI episodes in order to prevent mortality and progression of the disease.

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Post-treatment with JP-1302 protects against renal ischemia/reperfusion-induced acute kidney injury in rats

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2018.12.008 ◽

2019 ◽

Vol 139 (3) ◽

pp. 137-142 ◽

Cited By ~ 5

Author(s):

Takaomi Shimokawa ◽

Hidenobu Tsutsui ◽

Takeshi Miura ◽

Masashi Takama ◽

Kohei Hayashi ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Post Treatment ◽

Renal Ischemia

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Human amniotic epithelial cells ameliorate kidney damage in ischemia-reperfusion mouse model of acute kidney injury

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01917-y ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Yifei Ren ◽

Ying Chen ◽

Xizi Zheng ◽

Hui Wang ◽

Xin Kang ◽

...

Keyword(s):

Bone Marrow ◽

Acute Kidney Injury ◽

Renal Function ◽

Mouse Model ◽

Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Mouse Bone Marrow ◽

Tissue Integration

Abstract Background Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cell (hAEC) is an ideal stem cell source. Increasing evidence suggests that exosomes may act as critical cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs and their derived exosomes (hAECs-EXO) in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms. Methods The hAECs were primary cultured, and hAECs-EXO were isolated and characterized. An ischemic-reperfusion injury-induced AKI (IRI-AKI) mouse model was established to mimic clinical ischemic kidney injury with different disease severity. Mouse blood creatinine level was used to assess renal function, and kidney specimens were processed to detect cell proliferation, apoptosis, and capillary density. Macrophage infiltration was analyzed by flow cytometry. hAEC-derived exosomes (hAECs-EXO) were used to treat hypoxia-reoxygenation (H/R) injured HK-2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAECs-EXO were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results We found that systematically administered hAECs could improve mortality and renal function in IRI-AKI mice, decrease the number of apoptotic cells, prevent peritubular capillary loss, and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their source cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production, and immunomodulation. These findings demonstrated that paracrine of exosomes might be the key mechanism of hAECs in alleviating renal ischemia reperfusion injury. Conclusions We reported hAECs could improve survival and ameliorate renal injury in mice with IRI-AKI. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs are at least partially, through paracrine pathways. hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells, for patients with AKI.

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Successful Repair of Acute Type B and Retrograde Type A Aortic Dissection With Kidney Ischemia

Vascular and Endovascular Surgery ◽

10.1177/1538574417708133 ◽

2017 ◽

Vol 51 (5) ◽

pp. 342-345 ◽

Cited By ~ 1

Author(s):

Jeko M. Madjarov ◽

Michael G. Katz ◽

Hector Crespo-Soto ◽

Svetozar Madzharov ◽

Timothy Roush ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Aortic Dissection ◽

Renal Artery ◽

Kidney Injury ◽

Renal Ischemia ◽

Left Renal Artery ◽

Acute Type ◽

Type B ◽

Type A Aortic Dissection

Acute dissection of thoracic aorta carries a risk of renal ischemia followed by the development of a kidney failure. The optimal surgical and nonsurgical management of these patients, timing of intervention, and the factors predicting renal recovery are not well delineated and remain controversial. We present a case of acute type B thoracic aortic dissection with left kidney ischemia. Evaluation of renal function was performed by the means of internationally accepted Risk, Injury, Failure, Loss of kidney function, End stage kidney disease and Acute Kidney Injury Network classifications for acute kidney injury, renal duplex sonography, and intravascular ultrasound that demonstrated left renal artery dissection with a flap completely compressing the true lumen. The patient underwent thoracic endovascular aortic repair and left renal artery stent and recovered well. Six months later, at the follow-up visit, retrograde type A aortic dissection was found, which was successfully repaired. Reversal of renal ischemia after aortic dissection depends on the precise assessment of renal function and prompt intervention.

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Concordant Changes of Plasma and Kidney MicroRNA in the Early Stages of Acute Kidney Injury: Time Course in a Mouse Model of Bilateral Renal Ischemia-Reperfusion

PLoS ONE ◽

10.1371/journal.pone.0093297 ◽

2014 ◽

Vol 9 (4) ◽

pp. e93297 ◽

Cited By ~ 29

Author(s):

Melissa A. Bellinger ◽

James S. Bean ◽

Melissa A. Rader ◽

Kathleen M. Heinz-Taheny ◽

Jairo S. Nunes ◽

...

Keyword(s):

Acute Kidney Injury ◽

Mouse Model ◽

Time Course ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Early Stages

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Lack of Evidence for a Remote Effect of Renal Ischemia/Reperfusion Acute Kidney Injury on Outcome from Temporary Focal Cerebral Ischemia in the Rat

Journal of Cardiothoracic and Vascular Anesthesia ◽

10.1053/j.jvca.2012.06.012 ◽

2013 ◽

Vol 27 (1) ◽

pp. 71-78 ◽

Cited By ~ 5

Author(s):

Robert B. Yates ◽

Huaxin Sheng ◽

Hiroaki Sakai ◽

Daniel T. Kleven ◽

Noelle A. DeSimone ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia

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Amelioration of testicular damages in renal ischemia/reperfusion by berberine: An experimental study

International Journal of Reproductive BioMedicine ◽

10.18502/ijrm.v17i10.5488 ◽

2019 ◽

Author(s):

Firouzeh Gholampour ◽

Shabnam Malekpour Mansourkhani ◽

Seyed Mohammad Owji

Keyword(s):

Acute Kidney Injury ◽

Plasma Levels ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Plasma Testosterone ◽

Left Renal Artery ◽

Functional Disorders ◽

Urea Nitrogen ◽

Testosterone Concentration

Background: Ischemic acute kidney injury is associated with an inflammatory reaction. Objective: In the current study, berberine was assessed for its effect on the functional disorders and histological damages of testis induced by renal ischemia/reperfusion (I/R). Materials and Methods: Twenty-eight adult male Wistar rats (260-300 gr) were equally divided into four groups (n = 7/each): sham and I/R groups which received distilled water as well as berberine (BBR) and BBR + I/R groups which received berberine (15 mg/kg/day) orally seven days before the surgery. In both groups of sham and BBR, renal arteries were not clamped. Renal I/R was induced by occluding right and left renal artery for 45 min followed by a 24 hr reperfusion period. Blood samples were taken for determining the plasma levels of creatinine, urea nitrogen, FSH (follicle stimulating hormone), LH (luteinizing hormone), and testosterone. Then the rats were killed under deep anesthesia and the left testis was immediately isolated and preserved. Results: The renal I/R injury led to testicular histological damages accompanied with increased plasma levels of creatinine, urea nitrogen, LH, and FSH, as well decrease of plasma testosterone concentration at the end of 24 hr reperfusion (All p < 0.001, except for FSH p < 0.01). Berberine diminished histological damage to the testis and attenuated the increase in plasma creatinine, urea nitrogen, LH, FSH, and decrease in plasma testosterone concentration in the BBR + I/R group (All p < 0.001). Conclusion: These results suggest that ischemic acute renal failure induces functional disorders and tissue damages in testis of rat, which was improved through the administration of berberine. Key words: Ischemia/reperfusion, Acute kidney injury, Berberine, Testis, LH, FSH.

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Human amniotic epithelial cells improve kidney repair in ischemia-reperfusion mouse model of acute kidney injury

10.21203/rs.3.rs-28766/v1 ◽

2020 ◽

Author(s):

Yifei Ren ◽

Ying Chen ◽

Xizi Zheng ◽

Hui Wang ◽

Xin Kang ◽

...

Keyword(s):

Bone Marrow ◽

Acute Kidney Injury ◽

Renal Function ◽

Epithelial Cells ◽

Mouse Model ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Mouse Bone Marrow ◽

Tissue Integration

Abstract Background: Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and very limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cells (hAECs) are ideal alternative stem cell source for regenerative medicine. Increasing evidence suggests that hAEC-derived exosomes (hAECs-EXO) may act as novel cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms.Methods: The hAECs were primary cultured and hAECs-EXO were isolated and characterized. An ischemic renal injury mouse model was established to mimic different severity of the kidney injury. Mouse blood creatinine level was used to assess renal function and kidney specimens were processed to detect cell proliferation, apoptosis and angiogenesis. Immune cells infiltration was analyzed by flow cytometry. hAECs-EXO was used to treat hypoxia-reoxygenation (H/R) injured HK2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAEC exosomes were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results: We found that systematically administered hAECs could improve mortality and renal function in IRI mice; decrease the number of apoptotic cells; promote peritubular capillary regeneration and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their parent cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production and immunomodulation. These findings demonstrated that paracrine of exosomes might be a key mechanism by hAECs mediating kidney functional recovery in AKI.Conclusions: We first reported hAECs could improve mortality and renal repair in mice with ischemia-reperfusion injury. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs at least partially, through paracrine pathways. The renoprotective effects of hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells for patients with AKI.

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