Abstract P298: Finerenone Protects Against the Acute and Chronic Consequences of Renal Ischemia/reperfusion Injury

Introduction: One of the most common causes of acute kidney injury (AKI) is renal ischemia/reperfusion (IR). Mineralocorticoid receptor (MR) antagonism has shown beneficial effects against renal IR consequences. The potential benefit of novel non-steroidal MR antagonists such as finerenone has not been explored. Objective: Evaluate the efficacy of finerenone to prevent the acute and chronic consequences of ischemic AKI. Methods: For the acute study (24 hours), 18 rats were divided in: sham, rats subjected to bilateral renal ischemia of 25 min and rats that received three doses of finerenone at -48 h, -24 h and -1 h before the ischemia. For the chronic study (4 months), 21 rats were divided in: sham, rats with 45 min of bilateral ischemia and rats treated with Finerenone at day -2, -1 and 1h before IR. The left kidney was used for histology and the right kidney for molecular analysis. Results: After 24 h of reperfusion, the untreated IR rats presented a 3-fold increase in plasma creatinine, accompanied by 40% of tubules presenting cell detachment and casts. Kim-1 and NGAL mRNA levels were induced by 30-fold. In contrast, the rats that received finerenone presented normal creatinine and significantly fewer injured tubules (11%) and a less pronounced induction of kim-1 and NGAL (8-fold). After 4 months, the untreated IR rats developed chronic kidney disease (CKD), evidenced by kidney dysfunction, increased proteinuria (121.6 vs. 14.3 mg/24h in sham) and renal vascular resistance (16.8 vs. 11.4 mmHg/mL in sham). Tubular dilation, extensive tubule-interstitial fibrosis and an increase in kidney TGF-β and Collagen-I mRNA levels also characterized CKD. The transition from AKI to CKD was fully prevented by finerenone administration at the time of IR. Conclusion: Altogether, our data shows that finerenone is able to prevent AKI induced by IR as well as the chronic and progressive deterioration of kidney function and structure.

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Nicotinamide Mononucleotide Attenuates Renal Interstitial Fibrosis After AKI by Suppressing Tubular DNA Damage and Senescence

Frontiers in Physiology ◽

10.3389/fphys.2021.649547 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yan Jia ◽

Xin Kang ◽

Lishan Tan ◽

Yifei Ren ◽

Lei Qu ◽

...

Keyword(s):

Dna Damage ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Recovery Phase ◽

Tubular Cell ◽

Dna Damage And Repair ◽

Kidney Fibrosis ◽

Beneficial Effects

Acute kidney injury (AKI) is a worldwide health problem currently lacking therapeutics that directly promote renal repair or prevent the occurrence of chronic fibrosis. DNA damage is a feature of many forms of kidney injury, and targeting DNA damage and repair might be effective strategies for kidney protection in AKI. Boosting nicotinamide adenine dinucleotide (NAD+) levels is thought to have beneficial effects on DNA damage repair and fibrosis in other organs. However, no kidney-related studies of such effects have been performed to date. Here, we have shown that NMN (an NAD+ precursor) administration could significantly reduce tubular cell DNA damage and subsequent cellular senescence induced by hydrogen peroxide and hypoxia in human proximal tubular cells (HK-2 cells). The DNA damage inhibition, antiaging and anti-inflammatory effects of NMN were further confirmed in a unilateral ischemia-reperfusion injury (uIRI) mouse model. Most importantly, the antifibrosis activity of NMN was also shown in ischemic AKI mouse models, regardless of whether NMN was administered in advance or during the recovery phase. Collectively, these results suggest that NMN could significantly inhibit tubular cell DNA damage, senescence and inflammation. NMN administration might be an effective strategy for preventing or treating kidney fibrosis after AKI.

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Effect of sildenafil in renal ischemia/reperfusion injury in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502010000600006 ◽

2010 ◽

Vol 25 (6) ◽

pp. 490-495 ◽

Cited By ~ 24

Author(s):

Paulo José de Medeiros ◽

Arthur Villarim Neto ◽

Francisco Pignataro Lima ◽

Ítalo Medeiros Azevedo ◽

Layra Ribeiro de Sousa Leão ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Histopathological Examination ◽

Ischemia Reperfusion ◽

Left Kidney ◽

Renal Ischemia ◽

Renal Scintigraphy ◽

Control Group ◽

Left Renal Artery ◽

Differential Function ◽

The Right

PURPOSE: To evaluate the effect of sildenafil, administered prior to renal ischemia/reperfusion (I/R), by scintigraphy and histopathological evaluation in rats. METHODS: Twenty-four rats were divided randomly into two groups. They received 0.1 ml of 99mTechnetium-etilenodicisteine intravenous, and a baseline (initial) renal scintigraphy was performed. The rats underwent 60 minutes of ischemia by left renal artery clamping. The right kidney was not manipulated. The sildenafil group (n=12) received orally 1 mg/kg of sildenafil suspension 60 minutes before ischemia. Treatment with saline 0.9% in the control group (n=12). Half of the rats was assessed after 24 hours and half after seven days I/R, with new renal scintigraphy to study differential function. After euthanasia, kidneys were removed and subjected to histopathological examination. For statistical evaluation, Student t and Mann-Whitney tests were used. RESULTS: In the control group rats, the left kidneys had significant functional deficit, seven days after I/R, whose scintigraphic pattern was consistent with acute tubular necrosis, compared with the initial scintigraphy (p<0.05). Sildenafil treatment resulted in better differential function of the left kidneys 24h after reperfusion, compared with controls. Histopathologically, the left kidney of control rats (24 hours after I/R) showed a higher degree of cellular necrosis when compared with the sildenafil treated rats (p<0.05). CONCLUSION: Sildenafil had a protective effect in rat kidneys subjected to normothermic I/R, demonstrated by scintigraphy and histomorphometry.

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Targeting Ferroptosis Attenuates Interstitial Inflammation and Kidney Fibrosis

Kidney Diseases ◽

10.1159/000517723 ◽

2021 ◽

pp. 1-15

Author(s):

Lu Zhou ◽

Xian Xue ◽

Qing Hou ◽

Chunsun Dai

Keyword(s):

Mouse Models ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Kidney Fibrosis ◽

Ureter Obstruction ◽

Regulated Necrosis ◽

Dependent Form

Background: Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown. Objectives: The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis. Methods: Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated. Results: We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis. Conclusions: This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.

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Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

10.1101/2020.08.17.253252 ◽

2020 ◽

Author(s):

Caitriona M. McEvoy ◽

Sergi Clotet-Freixas ◽

Tomas Tokar ◽

Chiara Pastrello ◽

Shelby Reid ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Kidney Injury ◽

Tca Cycle ◽

Proteomics Analysis ◽

Beneficial Effects ◽

Kidney Perfusion

AbstractNormothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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Targeting HIF-1α to Prevent Renal Ischemia-Reperfusion Injury: Does It Work?

International Journal of Cell Biology ◽

10.1155/2018/9852791 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Kapil Sethi ◽

Kenny Rao ◽

Damien Bolton ◽

Oneel Patel ◽

Joseph Ischia

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Arterial Occlusion ◽

Small Animal ◽

Kidney Injury ◽

Renal Ischemia ◽

Metabolic Adaptation ◽

Critical Ischemia

Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1α via ischemic preconditioning (IPC) or drugs that simulate hypoxia (hypoxia-mimetics) has been investigated as a method to reduce IRI. While many promising chemical agents have been trialed for the prevention of IRI in small animal studies, all have failed in human trials. The aim of this review is to highlight the techniques and drugs that target HIF-1α and ameliorate IRI associated with renal ischemia. Developing a technique or drug that could reduce the risk of acute kidney injury associated with renal IRI would have an immediate worldwide impact on multisystem surgeries that would otherwise risk ischemic tissue injury.

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The Beneficial Effects of Tadalafil on Renal Ischemia-Reperfusion Injury in Rats

Urologia Internationalis ◽

10.1159/000321927 ◽

2011 ◽

Vol 86 (2) ◽

pp. 197-203 ◽

Cited By ~ 20

Author(s):

Mehmet Guzeloglu ◽

Fatih Yalcinkaya ◽

Soner Atmaca ◽

Alper Bagriyanik ◽

Suleyman Oktar ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Beneficial Effects ◽

Renal Ischemia Reperfusion Injury

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Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

Blood ◽

10.1182/blood-2011-02-338061 ◽

2011 ◽

Vol 118 (7) ◽

pp. 1934-1942 ◽

Cited By ~ 33

Author(s):

Aparna Krishnamoorthy ◽

Amrendra Kumar Ajay ◽

Dana Hoffmann ◽

Tae-Min Kim ◽

Victoria Ramirez ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

High Sensitivity ◽

Kidney Damage ◽

Therapeutic Interventions ◽

Mrna Levels ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Injury And Repair

AbstractIschemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

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Arginase-2 mediates renal ischemia-reperfusion injury

AJP Renal Physiology ◽

10.1152/ajprenal.00620.2016 ◽

2017 ◽

Vol 313 (2) ◽

pp. F522-F534 ◽

Cited By ~ 7

Author(s):

Wesley M. Raup-Konsavage ◽

Ting Gao ◽

Timothy K. Cooper ◽

Sidney M. Morris ◽

W. Brian Reeves ◽

...

Keyword(s):

Reperfusion Injury ◽

Blood Urea Nitrogen ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Arginase Activity ◽

Urea Nitrogen ◽

The Impact ◽

Novel Therapeutic

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient ( Arg2−/−) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection in renal IRI. Arg2−/− mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

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Which remote ischemic preconditioning protocol is favorable in renal ischemia-reperfusion injury in the rat?

Clinical Hemorheology and Microcirculation ◽

10.3233/ch-200916 ◽

2020 ◽

Vol 76 (3) ◽

pp. 439-451

Author(s):

Gabor Varga ◽

Souleiman Ghanem ◽

Balazs Szabo ◽

Kitti Nagy ◽

Noemi Pal ◽

...

Keyword(s):

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hematological Parameters ◽

Renal Ischemia ◽

Remote Ischemic Preconditioning ◽

Optimal Timing ◽

Delayed Effect ◽

Artery Cannulation ◽

The Right

BACKGROUND: The optimal timing of remote ischemic preconditioning (RIPC) in renal ischemia-reperfusion (I/R) injury is still unclear. We aimed to compare early- and delayed-effect RIPC with hematological, microcirculatory and histomorphological parameters. METHODS: In anesthetized male CrI:WI Control rats (n = 7) laparotomy and femoral artery cannulation were performed. In I/R group (n = 7) additionally a 45-minute unilateral renal ischemia with 120-minute reperfusion was induced. The right hind-limb was strangulated for 3×10 minutes (10-minute intermittent reperfusion) 1 hour (RIPC-1 group, n = 7) or 24 hour (RIPC-24 group, n = 6) prior to the I/R. Hemodynamic, hematological parameters and organs’ surface microcirculation were measured. RESULTS: Control and I/R group had the highest heart rate (p < 0.05 vs base), while the lowest mean arterial pressure (p < 0.05 vs RIPC-1) were found in the RIPC-24 group. The highest microcirculation values were measured in the I/R group (liver: p < 0.05 vs Control). The leukocyte count increased in I/R group (base: p < 0.05 vs Control), also this group’s histological score was the highest (p < 0.05 vs Control). The RIPC-24 group had a significantly lower score than the RIPC-1 (p = 0.0025 vs RIPC-1). CONCLUSION: Renal I/R caused significant functional and morphological, also in the RIPC groups. According to the histological examination the delayed-effect RIPC method was more effective.

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