Renal ischemia/reperfusion induces prominent progressive kidney disease in diabetic mice.

Acute kidney injury (AKI) is a public health concern associated with high rates of mortality, even in milder cases. One of the reasons for the difficulty in managing AKI in patients is due to its association with pre-existing comorbidities, such as diabetes. In fact, diabetes increases the susceptibility to develop more severe AKI after renal ischemia. However, the long-term effects of this association are not known. Thus, an experimental model to evaluate the chronic effects of renal ischemia/reperfusion (IR) in STZ-treated mice was analyzed. We focused on the glomerular and tubulointerstitial damage, as well as kidney function and metabolic profile. It was found that pre-existing diabetes may potentiate progressive kidney disease after AKI, mainly by exacerbating pro-inflammatory and sustaining fibrotic responses and altering renal glucose metabolism. For our knowledge, this is the first report that highlights the long-term effects of renal IR on diabetes. The findings of this study can support the management of AKI in clinical practice.

Scutellarin alleviates renal ischemia-reperfusion injury by inhibiting the MAPK pathway and pro-inflammatory macrophage polarization.

Renal ischemia-reperfusion injury (IRI) is an integral process in renal transplantation, which results in compromised graft survival. Macrophages play an important role in both the early inflammatory period and late fibrotic period in response to IRI. In this study, we investigated whether scutellarin (SCU) could protect against renal IRI by regulating macrophage polarization. Mice were given SCU (5-50 mg/kg) by gavage 1 h earlier, followed by a unilateral renal IRI. Renal function and pathological injury were assessed 24 h after reperfusion. The results showed that administration of 50 mg/kg SCU significantly improved renal function and renal pathology in IRI mice. In addition, SCU alleviated IRI-induced apoptosis. Meanwhile, it reduced macrophage infiltration and inhibited pro-inflammatory macrophage polarization. Moreover, in RAW 264.7 cells and primary bone marrow-derived macrophages (BMDMs) exposed to SCU, we found that 150 µM SCU inhibited these cells to polarize to an inflammatory phenotype induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, SCU has no influence on anti-inflammatory macrophage polarization in vivo and in vitro induced by in interleukin-4 (IL-4). Finally, we explored the effect of SCU on the activation of the mitogen-activated protein kinase (MAPK) pathway both in vivo and in vitro. We found that SCU suppressed the activation of the MAPK pathway, including the extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38. Our results demonstrated that SCU protects the kidney against IRI by inhibiting macrophage infiltration and polarization toward pro-inflammatory phenotype via the MAPK pathway, suggesting that SCU may be therapeutically important in treatment of IRI.

The roles of TRPC6 in renal tubular disorders: a narrative review.

The transient receptor potential canonical 6 (TRPC6) channel, a nonselective cation channel that allows the passage of Ca2+, plays an important role in renal diseases. TRPC6 is activated by Ca2+ influx, oxidative stress, and mechanical stress. Studies have shown that in addition to glomerular diseases, TRPC6 can contribute to renal tubular disorders, such as acute kidney injury, renal interstitial fibrosis, and renal cell carcinoma (RCC). However, the tubule-specific physiological functions of TRPC6 have not yet been elucidated. Its pathophysiological role in ischemia/reperfusion (I/R) injury is debatable. Thus, TRPC6 may have dual roles in I/R injury. TRPC6 induces renal fibrosis and immune cell infiltration in a unilateral ureteral obstruction (UUO) mouse model. Additionally, TRPC6 overexpression may modify G2 phase transition, thus altering the DNA damage checkpoint, which can cause genomic instability and RCC tumorigenesis and can control the proliferation of RCC cells. This review highlights the importance of TRPC6 in various conditions of the renal tubular system. To better understand certain renal disorders and ultimately identify new therapeutic targets to improve patient care, the pathophysiology of TRPC6 must be clarified.

Selenoprotein-P1 (SEPP1) Expression in Human Proximal Tubule Cells after Ischemia-Reperfusion Injury: An In Vitro Model.

Background and Objectives: Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium transporter, mainly released by the liver, has emerged as a promising plasmatic biomarker of AKI as a consequence of cardio-surgery operations. The aim of the present study was to investigate, on an in vitro model of hypoxia induced in renal tubular cells, HK-2, the effects of sodium selenite (Na2SeO3) and to evaluate the expression of SEPP1 as a marker of injury. Materials and Methods: HK-2 cells were pre-incubated with 100 nM Na2SeO3 for 24 h, and then, treated for 24 h with CoCl2 (500 µM), a chemical hypoxia inducer. The results were derived from an ROS assay, MTT, and Western blot analysis. Results: The pre-treatment determined an increase in cells' viability and a reduction in reactive oxygen species (ROS), as shown by MTT and the ROS assay. Moreover, by Western blot an increase in SEPP1 expression was observed after hypoxic injury as after adding sodium selenite. Conclusions: Our preliminary results shed light on the possible role of selenium supplementation as a means to prevent oxidative damage and to increase SEPP1 after acute kidney injury. In our in vitro model, SEPP1 emerges as a promising biomarker of kidney injury, although further studies in vivo are necessary to validate our findings.

Protective effects of pioglitazone in renal ischemia-reperfusion injury (RIRI): focus on oxidative stress and inflammation.

BACKGROUND: Renal ischemia-reperfusion injury (RIRI) is a critical phenomenon that compromises renal function and is the most serious health concern related to acute kidney injury (AKI). Pioglitazone (Pio) is a known agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ). PPAR-γ is a nuclear receptor that regulates genes involved in inflammation, metabolism, and cellular differentiation. Activation of PPAR-γ is associated with antiinflammatory and antioxidant effects, which are relevant to the pathophysiology of RIRI. This study aimed to investigate the protective effects of Pio in RIRI, focusing on oxidative stress and inflammation. METHODS: We conducted a comprehensive literature search using electronic databases, including PubMed, ScienceDirect, Web of Science, Scopus, and Google Scholar. RESULTS: The results of this study demonstrated that Pio has antioxidant, anti-inflammatory, and anti-apoptotic activities that counteract the consequences of RIRI. The study also discussed the underlying mechanisms, including the modulation of various pathways such as TNF-α, NF-κB signaling systems, STAT3 pathway, KIM-1 and NGAL pathways, AMPK phosphorylation, and autophagy flux. Additionally, the study presented a summary of various animal studies that support the potential protective effects of Pio in RIRI. CONCLUSION: Our findings suggest that Pio could protect the kidneys from RIRI by improving antioxidant capacity and decreasing inflammation. Therefore, these findings support the potential of Pio as a therapeutic strategy for preventing RIRI in different clinical conditions.

Multi-omics analysis of renal vein serum with Ischemia-Reperfusion injury.

BACKGROUND: Acute kidney injury (AKI) is frequently caused by renal ischemia-reperfusion injury (IRI). Identifying potential renal IRI disease biomarkers would be useful for evaluating AKI severity. OBJECTIVE: We used proteomics and metabolomics to investigate the differences in renal venous blood between ischemic and healthy kidneys in an animal model by identifying differentially expressed proteins (DEPs) and differentially expressed protein metabolites (DEMs). METHODS: Nine pairs of renal venous blood samples were collected before and at 20, 40, and 60 min post ischemia. The ischemia time of Group A, B and C was 20,40 and 60 min. The proteome and metabolome of renal venous blood were evaluated to establish the differences between renal venous blood before and after ischemia. RESULTS: We identified 79 common DEPs in all samples of Group A, 80 in Group B, and 131 in Group C. Further common DEPs among all three groups were Tyrosineprotein kinase, GPR15LG, KAZALD1, ADH1B. We also identified 81, 64, and 83 common DEMs in each group respectively, in which 30 DEMs were further common to all groups. Bioinformatic analysis of the DEPs and DEMs was conducted. CONCLUSION: This study demonstrated that different pathological processes occur during short- and long-term renal IRI. Tyrosine protein kinase, GPR15LG, Kazal-type serine peptidase inhibitor domain 1, and all-trans-retinol dehydrogenase are potential biomarkers of renal IRI.

Microwave Scissors-Based Sutureless Laparoscopic Partial Nephrectomy Versus Conventional Open Partial Nephrectomy in a Porcine Model: Usefulness and Complications.

BACKGROUND: This study aimed to compare the benefits and safety of microwave scissors-based sutureless laparoscopic partial nephrectomy (MSLPN) with those of conventional open partial nephrectomy (cOPN). METHODS: Each kidney in nine pigs underwent MSLPN using microwave scissors (MWS) via transperitoneal laparoscopy or cOPN via retroperitoneal open laparotomy. The kidney's lower and upper poles were resected under temporary hilar-clamping. The renal calyces exposed during renal resections were sealed and transected using MWS in MSLPN and were sutured in cOPN. For MWS, the generator's power output was 60 W. Data on procedure time (PT), ischemic time (IT), blood loss (BL), normal nephron loss (NNL), and extravasation during retrograde pyelogram were compared between the two techniques. RESULTS: The authors successfully performed 22 MSLPNs and 10 cOPNs. Compared with cOPN, MSLPN was associated with significantly lower PT (median, 9.2 vs 13.0 min; p = 0.026), IT (median, 5.9 vs 9.0 min; p < 0.001), BL (median, 14.4 vs 38.3 mL; p = 0.043), and NNL (median, 7.6 vs 9.4 mm; p = 0.004). However, the extravasation rate was higher in the MSLPN group than in the cOPN group (54.5 % [n = 12] vs 30.0 % [n = 3]), albeit without a significant difference (p = 0.265). Pelvic stenosis occurred in one MSLPN procedure that involved deep lower pole resection near the kidney hilum. CONCLUSIONS: The study data show that MSLPN can improve intraoperative outcomes while reducing technical demands for selected patients with non-hilar-localized renal tumors. However, renal calyces, if violated, should be additionally sutured to prevent urine leakage.

Delivery of exogenous miR-19b by Wharton's Jelly Mesenchymal Stem Cells attenuates transplanted kidney ischemia/reperfusion injury by regulating cellular metabolism.

Renal ischemia-reperfusion injury (IRI) frequently occurs following kidney transplantation, and exosomes derived from umbilical cord mesenchymal stem cells (WJ-MSC-Exos) have shown promise in treating IRI in transplanted kidneys. Our study delved into the potential mechanism of WJ-MSC-Exos in ameliorating IRI in transplanted kidneys, revealing that miR-19b is abundantly present in WJ-MSC-Exos. Both in vivo and in vitro experiments demonstrated that the absence of miR-19b abolished the protective effects of WJ-MSC-Exos against renal IRI. Mechanistically, miR-19b suppressed glycogen synthase kinase-3ß (GSK3ß) expression, thereby stabilizing PDXK protein through direct binding. Treatment with WJ-MSC-Exos led to reduced PDXK levels and enhanced pyridoxine accumulation, ultimately mitigating IRI in transplanted kidneys and I/R-induced HK2 cell apoptosis. These findings elucidate the underlying mechanism of WJ-MSC-Exos in alleviating IRI in transplanted kidneys, unveiling novel therapeutic targets for post-kidney transplantation IRI and providing a solid theoretical foundation for the clinical application of WJ-MSC-Exos in IRI treatment post-transplantation.

Endovascular salvage of occluded renal artery after >15 hours of ischemic time.

In severe cases of acute traumatic injury to the kidney, immediate intervention is necessary to avoid irreversible ischemic damage. This case involves a 24-year-old woman who presented with signs of right renal devascularization after a high-speed all-terrain vehicle accident. Due to transport from an outside hospital, there was >15-hour delay before evaluation by vascular surgery. Considering her young age, we elected to salvage this patient's kidney via percutaneous endovascular stenting to mitigate any further prolongation of renal artery occlusion and prevent long-term sequelae. After intervention, her acute kidney injury resolved, and her creatinine levels normalized. As illustrated in this case, recovery of the renal parenchyma remains a possibility despite an extended warm ischemic time, providing evidence for future young patients to be considered for renal salvage.

Alpha-cyperone mitigates renal ischemic injury via modulation of HDAC-2 expression in diabetes: Insights from molecular dynamics simulations and experimental evaluation.

Chronic diabetes mellitus is reported to be associated with acute kidney injury. The enzyme histone deacetylase-2 (HDAC-2) was found to be upregulated in diabetes-related kidney damage. Alpha-cyperone (α-CYP) is one of the active ingredients of Cyperus rotundus that possesses antioxidant and anti-inflammatory effects. We evaluated the effect of α-CYP on improving oxidative stress and tissue inflammation following renal ischemia/reperfusion (I/R) injury in diabetic rats. The effect of α-CYP on HDAC-2 expression in renal homogenates and in the NRK-52 E cell line was evaluated following renal I/R injury and high glucose conditions, respectively. Molecular docking was used to investigate the binding of α-CYP with the HDAC-2 active site. Both renal function and oxidative stress were shown to be impaired in diabetic rats due to renal I/R injury. Significant improvements in kidney/body weight ratio, creatinine clearance, serum creatinine, blood urea nitrogen (BUN), and uric acid were observed in diabetic rats treated with α-CYP (50 mg/kg) two weeks prior to renal I/R injury. α-CYP treatment also improved histological alterations in renal tissue and lowered levels of malondialdehyde, myeloperoxidase, and hydroxyproline. Treatment with α-CYP suppressed the increased HDAC-2 expression in the renal tissue of diabetic rats and in the NRK-52 E cell line. The molecular docking reveals that α-CYP binds to HDAC-2 with good affinity, ascertained by molecular dynamics simulations and binding free energy analysis. Overall, our data suggest that α-CYP can effectively prevent renal injury in diabetic rats by regulating oxidative stress, tissue inflammation, fibrosis and inhibiting HDAC-2 activity.

Evaluating Acetate as a Renoprotective Agent After Kidney Ischemia in a Porcine Model.

Objective: Renoprotection from reperfusion injury appears to be conferred by HIF-2a activation, which can be stimulated by exogenous acetate administration. The study objective was to assess whether administration of acetate in a porcine model can mitigate kidney injury related to ischemia-reperfusion after renal hilar occlusion. Methods: A porcine single-kidney model was created by performing a laparoscopic nephrectomy followed by animal recovery. After 2 days, the animals underwent laparoscopic hilar dissection. Block randomization was used to assign pigs into one of four experimental groups. One treatment block of pigs received 150 mEq of sodium acetate intravenously during 90 minutes of en bloc occlusion of the renal hilum (herein noted as "cross-clamping"). Another block received 0.75 g/kg of oral sodium acetate for 3 days prior to cross-clamping. A third block received no acetate and underwent hilar dissection without cross-clamping (negative control). The final block received no acetate and underwent cross-clamping (positive control). Serum creatinine was used to estimate renal function post-nephrectomy. Results: A total of 16 animals (4 pigs in each group) completed the study protocol. Median pig weight was 34.6 kg. One pig receiving IV acetate was excluded from the final analysis because of unrecoverable renal failure after cross-clamping. There was a significantly lower mean serum creatinine for the IV acetate group compared with the positive control group 72 hours after cross-clamping (p = 0.012). The same effect was not observed for the pigs receiving oral acetate. By day 7, renal function had recovered without significant difference in all groups. Conclusions: We observed that the administration of intravenous acetate conferred a significant renoprotective benefit in our single kidney ischemia-reperfusion porcine model 72 hours after hilar occlusion. This work is hypothesis-generating, and further work in human subjects undergoing renal hilar occlusion during partial nephrectomy is warranted.

The effect of 11th rib excision on perioperative outcomes in patients undergoing partial nephrectomy for upper pole renal tumors.

INTRODUCTION: We aimed to evaluate the effect of eleven11th rib resection.on the perioperative period TRIFECTA criteria in patients who underwent retroperitoneal partial nephrectomy (PN) with the diagnosis of upper pole kidney tumors. MATERIALS AND METHODS: We conducted a retrospective analysis of the data of the patients who underwent Open PN for upper pole renal masses between 2018 and 2023. The patients were divided into two groups: PN with rib resection and PN without rib resection. The demographic characteristics, tumor sizes, PADUA scores, warm-cold renal ischemia times, mass excision and tumor bed suturing times, histopathological tumor type and surgical margin positivity of the patients were examined. Both groups were evaluated comparatively based on this data. RESULTS: The renal nephrometry scores of the two groups were similar. The total renal ischemia time was significantly shorter in the patients who underwent a rib resection than in those who did not (p < 0.001). Both the tumor excision and tumor bed suturing times were significantly shorter in the group that underwent a rib resection than in the group that did not (p < 0.001). The Clavien-Dindo complication grades were statistically similar between the two groups. CONCLUSION: Complex in nature and high-risk renal masses located in the upper pole of the kidney, partial nephrectomy performed with an 11th rib resection can be considered a reliable surgical option with a shorter ischemia time, supporting the preservation of long-term renal function.

Does cardiac impairment develop in ischemic renal surgery in rats depending on the reperfusion time?

Background: Renal dysfunction is known to cause heart failure. However, renal dysfunction associated with kidney surgeries (mediated by reperfusion injury) that affects the cardiac physiological function, especially during the recovery and repair phase of renal surgery is unknown. Method: Male Wistar rats (238 ± 18 g) were subjected to renal sham and ischemia-reperfusion (IR-bilateral clamping for 15 min/45 min and reperfusion for 24 h/48 h/7 days) surgeries. At the end of the experiment, the heart was isolated from the animal (to exclude neurohormonal influence) and perfused for 60 min with Krebs-Hanseleit buffer to study the physiological changes. Result: Renal artery bilateral occlusion for 45 min that creates ischemia, followed by 24 h of reperfusion did not impart any significant cardiac physiological functional decline but 48 h of reperfusion exhibited a significant decline in cardiac hemodynamic indices (Rate pressure product in x104 mmHg*beats/min: Sham- 3.53 ± 0.19, I45_R48-2.82 ± 0.21) with mild tissue injury. However, 7 days of reperfusion inflict significant physiological decline (Rate pressure product in x104 mmHg*beats/min - 2.5 ± 0.14) and tissue injury (Injury score- 4 ± 1.5) in isolated rat hearts. Interestingly, when the renal artery bilateral occlusion time was reduced to 15 min the changes in the hearts were negligible after 7 days. Cellular level exploration reveals a positive relation between functional deterioration of mitochondria and elevated mitochondrial oxidative stress and inflammation with cardiac physiological decline and injury linked with renal ischemia-reperfusion surgery. Conclusion: Cardiac functional decline associated with renal surgery is manifested during renal repair or recovery. This decline depends on cardiac mitochondrial health, which is negatively influenced by the renal IR mediators and kidney function.

Recent Advances of MSCs in Renal IRI: From Injury to Renal Fibrosis.

Renal fibrosis is a pathological endpoint of maladaptation after ischemia-reperfusion injury (IRI), and despite many attempts, no good treatment has been achieved so far. At the core of renal fibrosis is the differentiation of various types of cells into myofibroblasts. MSCs were once thought to play a protective role after renal IRI. However, growing evidence suggests that MSCs have a two-sided nature. In spite of their protective role, in maladaptive situations, MSCs start to differentiate towards myofibroblasts, increasing the myofibroblast pool and promoting renal fibrosis. Following renal IRI, it has been observed that Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) and Renal Resident Mesenchymal Stem Cells (RR-MSCs) play important roles. This review presents evidence supporting their involvement, discusses their potential mechanisms of action, and suggests several new targets for future research.

Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy.

Mitochondrial dysfunction is recognized as a pivotal contributor to the pathogenesis of renal ischemia-reperfusion (IR) injury. Mitophagy, the process responsible for removing damaged protein aggregates, stands as a critical mechanism safeguarding cells against IR injury. Currently, the role of deubiquitination in regulating mitophagy still needs to be completely elucidated. This study aimed to evaluate the impact of ubiquitin-specific peptidase 14 (Usp14), a deubiquitinase, in IR injury by influencing mitophagy. Utilizing a murine model of renal IR injury, Usp14 silencing was found to ameliorate kidney injury, leading to decreased levels of serum creatinine and blood urea nitrogen, alongside diminished oxidative stress and inflammation. In renal epithelial cells subjected to hypoxia/reoxygenation (H/R), Usp14 knockdown increased cell viability and reduced apoptosis. Further mechanistic studies revealed that Usp14 interacted with and deubiquitinated transcription factor AP-2 alpha (Tfap2a), thereby suppressing its downstream target gene, TANK binding kinase 1 (Tbk1), to influence mitophagy. Tfap2a overexpression or Tbk1 inhibition reversed the protective effects of Usp14 silencing on renal tubular cell injury and its facilitation of mitophagy. In summary, our study demonstrated the renoprotective role of Usp14 knockdown in mitigating renal IR injury by promoting Tfap2a-mediated Tbk1 upregulation and mitophagy. These findings advocate for exploring Usp14 inhibition as a promising therapeutic avenue for mitigating IR injury, primarily by enhancing the clearance of damaged mitochondria through augmented mitophagy.

Hippo pathway activated by circulating reactive oxygen species mediates cardiac diastolic dysfunction after acute kidney injury.

Acute kidney injury (AKI) can cause distal cardiac dysfunction; however, the underlying mechanism is unknown. Oxidative stress is proved prominent in AKI-induced cardiac dysfunction, and a possible bridge role of oxidative-stress products in cardio-renal interaction has been reported. Therefore, this study aimed to investigate the critical role of circulating reactive oxygen species (ROS) in mediating cardiac dysfunction after bilateral renal ischemia-reperfusion injury (IRI). We observed the diastolic dysfunction in the mice following renal IRI, accompanied by reduced ATP levels, oxidative stress, and branched-chain amino acids (BCAA) accumulation in the heart. Notably, ROS levels showed a sequential increase in the kidneys, circulation, and heart. Treatment with tempol, an ROS scavenger, significantly restored cardiac diastolic function in the renal IRI mice, corroborating the bridge role of circulating ROS. Accumulating evidence has identified oxidative stress as upstream of Mst1/Hippo in cardiac injury, which could regulate the expression of downstream genes related to mitochondrial quality control, leading to lower ATP, higher ROS and metabolic disorder. To verify this, we examined the activation of the Mst1/Hippo pathway in the heart of renal IRI mice, which was alleviated by tempol treatment as well. In vitro, analysis revealed that Mst1-knockdown cardiomyocytes could be activated by hydrogen peroxide (H2O2). Analysis of Mst1-overexpression cardiomyocytes confirmed the critical role of the Mst1/Hippo pathway in oxidative stress and BCAA dysmetabolism. Therefore, our results indicated that circulating ROS following renal IRI activates the Mst1/Hippo pathway of myocardium, leading to cardiac oxidative stress and diastolic dysfunction. This finding provides new insights for the clinical exploration of improved treatment options for cardiorenal syndrome.

Potential therapeutic applications of circular RNA in acute kidney injury.

Acute kidney injury (AKI) is a common clinical syndrome characterized by a rapid deterioration in renal function, manifested by a significant increase in creatinine and a sharp decrease in urine output. The incidence of morbidity and mortality associated with AKI is on the rise, with most patients progressing to chronic kidney disease or end-stage renal disease. Treatment options for patients with AKI remain limited. Circular RNA (circRNA) is a wide and diverse class of non-coding RNAs that are present in a variety of organisms and are involved in gene expression regulation. Studies have shown that circRNA acts as a competing RNA, is involved in disease occurrence and development, and has potential as a disease diagnostic and prognostic marker. CircRNA is involved in the regulation of important biological processes, including apoptosis, oxidative stress, and inflammation. This study reviews the current status and progress of circRNA research in the context of AKI.

Role of cAMP/pCREB and GSK-3ß/NF-κB p65 signaling pathways in the renoprotective effect of mirabegron against renal ischemia-reperfusion injury in rats.

Acute kidney injury and other renal disorders are thought to be primarily caused by renal ischemia-reperfusion (RIR). Cyclic adenosine monophosphate (cAMP) has plenty of physiological pleiotropic effects and preserves tissue integrity and functions. This research aimed to examine the potential protective effects of the ß3-adrenergic receptors agonist mirabegron in a rat model of RIR and its underlying mechanisms. Male rats enrolled in this work were given an oral dose of 30 mg/kg mirabegron for two days before surgical induction of RIR. Renal levels of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), cAMP, cAMP-responsive element binding protein (pCREB), and glycogen synthase kinase-3 beta (GSK-3ß) were assessed along with blood urea nitrogen and serum creatinine. Additionally, caspase-3 and nuclear factor-kappa B (NF-κB) p65 were explored by immunohistochemical analysis. Renal specimens were inspected for histopathological changes. RIR led to renal tissue damage with elevated blood urea nitrogen and serum creatinine levels. The renal KIM-1, MCP-1, TNF-α, and GSK-3ß were significantly increased, while IL-10, cAMP, and pCREB levels were reduced. Moreover, upregulation of caspase-3 and NF-κB p65 protein expression was seen in RIR rats. Mirabegron significantly reduced kidney dysfunction, histological abnormalities, inflammation, and apoptosis in the rat renal tissues. Mechanistically, mirabegron mediated these effects via modulation of cAMP/pCREB and GSK-3ß/NF-κB p65 signaling pathways. Mirabegron administration could protect renal tissue and maintain renal function against RIR.

LncRNA HMOX1 alleviates renal ischemia-reperfusion-induced ferroptotic injury via the miR-3587/HMOX1 axis.

Emerging evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in renal ischemia reperfusion (RIR) injury. However, the specific mechanisms by which lncRNAs regulate ferroptosis in renal tubular epithelial cells remain largely unknown. The objective of this study was to investigate the biological function of lncRNA heme oxygenase 1 (lnc-HMOX1) in RIR and its potential molecular mechanism. Our findings demonstrated that the expression of HMOX1-related lnc-HMOX1 was reduced in renal tubular epithelial cells treated with hypoxia-reoxygenation (HR). Furthermore, the over-expression of lnc-HMOX1 mitigated ferroptotic injury in renal tubular epithelial cells in vivo and in vitro. Mechanistically, lnc-HMOX1, as a competitive endogenous RNA (ceRNA), promoted the expression of HMOX1 by sponging miR-3587. Furthermore, the inhibition of HMOX1 effectively impeded the aforementioned effects exerted by lnc-HMOX1. Ultimately, the inhibitory or mimic action of miR-3587 reversed the promoting or refraining influence of silenced or over-expressed lnc-HMOX1 on ferroptotic injury during HR. In summary, our findings contribute to a comprehensive comprehension of the mechanism underlying ferroptotic injury mediated by lnc-HMOX1 during RIR. Significantly, we identified a novel lnc-HMOX1-miR-3587-HMOX1 axis, which holds promise as a potential therapeutic target for RIR injury.

Role of mitochondria in renal ischemia-reperfusion injury.

Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) has a high morbidity and mortality, representing a worldwide problem. The kidney is an essential organ of metabolism that has high blood perfusion and is the second most mitochondria-rich organ after the heart because of the high ATP demands of its essential functions of nutrient reabsorption, acid-base and electrolyte balance, and hemodynamics. Thus, these energy-intensive cells are particularly vulnerable to mitochondrial dysfunction. As the bulk of glomerular ultrafiltrate reabsorption by proximal tubules occurs via active transport, the mitochondria of proximal tubules must be equipped for detecting and responding to fluctuations in energy availability to guarantee efficient basal metabolism. Any insults to mitochondrial quality control mechanisms may lead to biological disruption, blocking the clearance of damaged mitochondria and resulting in morphological change and tissue dysfunction. Extensive research has shown that mitochondria have pivotal roles in acute kidney disease, so in this article, we discuss the role of mitochondria, their dynamics and mitophagy in renal ischemia-reperfusion injury.