Acute Kidney Injury In Rats Research Articles

Protective effects of astaxanthin solid lipid nanoparticle as a promising candidate against acute kidney injury in rats.

Acute kidney injury (AKI) is a sudden onset of renal injury that occurs within a few hours or days. Ischemia-reperfusion (IR) is a major cause of AKI. There are multiple dysregulated mechanisms behind the pathogenesis of AKI and IR which urges the need for finding multi-targeting therapies. Natural products are multi-targeting agents with promising sources of anti-inflammation, antioxidant, and antiapoptosis. Among them, astaxanthin (AST) is a keto-carotenoid with a high antioxidant potential. Using solid lipid nanoparticles (SLNs) as a novel formulation of AST helps to increase its efficacy and reduce side effects against AKI. After SLN preparation and loading of AST, the physicochemical properties were evaluated, using scanning electron microscopy (SEM) and dynamic light scattering (DLS) tests. For the in vivo study, 28 rats were divided into four groups, including sham, ischemia/reperfusion (I/R), and groups receiving protective and daily doses of AST-SLN (5 and 10 mg/kg, i.p.) during all 5 days before ischemia. Exactly 24 h after ischemia, kidneys were isolated for histological studies, and also, serum levels of catalase (CAT), glutathione (GSH), nitrite, blood urea, and creatinine were measured. The results indicated that intraperitoneal administration of SLN-AST reduced oxidative stress by decreasing serum nitrite levels, while increasing CAT and GSH. SLN-AST also improved renal function by decreasing serum urea and creatinine and preventing tissue damage. Therefore, SLN-AST could be a hopeful adjuvant candidate to prevent AKI by modulating renal function, preventing tissue damage, and through antioxidant mechanisms.

Dexmedetomidine ameliorates acute kidney injury by regulating mitochondrial dynamics via the α2-AR/SIRT1/PGC-1α pathway activation in rats

BackgroundSepsis-associated acute kidney injury (AKI) is a serious complication of systemic infection with high morbidity and mortality in patients. However, no effective drugs are available for AKI treatment. Dexmedetomidine (DEX) is an alpha 2 adrenal receptor agonist with antioxidant and anti-apoptotic effects. This study aimed to investigate the therapeutic effects of DEX on sepsis-associated AKI and to elucidate the role of mitochondrial dynamics during this process.MethodsA lipopolysaccharide (LPS)-induced AKI rat model and an NRK-52E cell model were used in the study. This study investigated the effects of DEX on sepsis-associated AKI and the molecular mechanisms using histologic assessment, biochemical analyses, ultrastructural observation, western blotting, immunofluorescence, immunohistochemistry, qRT-PCR, flow cytometry, and si-mRNA transfection.ResultsIn rats, the results showed that administration of DEX protected kidney structure and function from LPS-induced septic AKI. In addition, we found that DEX upregulated the α2-AR/SIRT1/PGC-1α pathway, protected mitochondrial structure and function, and decreased oxidative stress and apoptosis compared to the LPS group. In NRK-52E cells, DEX regulated the mitochondrial dynamic balance by preventing intracellular Ca2+ overloading and activating CaMKII.ConclusionsDEX ameliorated septic AKI by reducing oxidative stress and apoptosis in addition to modulating mitochondrial dynamics via upregulation of the α2-AR/SIRT1/PGC-1α pathway. This is a confirmatory study about DEX pre-treatment to ameliorate septic AKI. Our research reveals a novel mechanistic molecular pathway by which DEX provides nephroprotection.

Molecular mechanisms of endoplasmic reticulum stress-mediated acute kidney injury in juvenile rats and the protective role of mesencephalic astrocyte-derived neurotrophic factor.

This study examined the role of endoplasmic reticulum stress in pediatric acute kidney injury and the therapeutic effect of midbrain astrocyte-derived neurotrophic factor. Two-week-old Sprague-Dawley rats were divided into: Sham, ischemia-reperfusion injury-induced acute kidney injury (AKI), mesencephalic astrocyte-derived neurotrophic factor (MANF)-treated, tauroursodeoxycholic acid (TUDCA)-treated. Analyses were conducted 24h post-treatment. Serum creatinine, cystatin C, Albumin, MANF levels were measured, cytokine concentrations in serum and renal tissues were determined using a Luminex assay. Histopathology was assessed via light and electron microscopy. Western blotting and RT-qPCR analyzed markers for oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, and autophagy. HK-2 cells underwent hypoxia/reoxygenation (H/R) to simulate AKI and were treated with MANF or TUDCA. AKI rats had increased serum creatinine, cystatin C, and inflammatory cytokines, along with significant renal damage, and showed loose and swollen ER structures, reduced cell proliferation, and elevated levels of IRE1, PERK, ATF6, CHOP, LC3-II/I, KIM-1, TLR4, JNK, and NF-κB. MANF treatment reduced these biomarkers and protein levels, improved ER structure and cell proliferation, alleviated oxidative stress, apoptosis, ER stress, and inhibited JNK/TLR4/NF-κB signaling. In HK-2 cells, MANF reduced ER stress and inflammation post-H/R exposure. MANF treatment alleviates ER stress, oxidative stress, apoptosis, and inflammation in pediatric AKI, improving renal function and morphology.

The Nephroprotective Effect of Punica granatum Peel Extract on LPS-Induced Acute Kidney Injury

Sepsis is an exaggerated immune response resulting from systemic inflammation, which can damage tissues and organs. Acute kidney injury has been detected in at least one-third of patients with sepsis. Sepsis-associated acute kidney injury increases the risk of a secondary infection. Rapid diagnosis and appropriate initiation of antibiotics can significantly reduce mortality and morbidity. However, microorganisms are known to develop resistance to antibiotics. Estimations indicate that the annual casualties caused by microbial resistance will surpass cancer fatalities by 2050. The prevalence of bacterial infections and their growing antibiotic resistance has brought immediate attention to the search for novel treatments. Plant-derived supplements contain numerous bioactive components with therapeutic potential against a variety of conditions, including infections. Punica granatum peel is rich in phenolic compounds. The purpose of this study was to determine the anti-inflammatory and anti-bacterial properties of P. granatum peel extract (PGPE) on lipopolysaccharide (LPS)-induced acute kidney injury. Experimental groups were Control, LPS (10 mg/kg LPS, intraperitoneally), PGPE100, and PGPE300 (100 and 300 mg/mL PGPE via oral gavage, respectively, for 7 days). According to biochemical results, serum blood urea nitrogen (BUN), creatinine (Cr) and C-reactive protein (CRP), kidney tissue thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) levels significantly decreased in the PGPE groups compared to the LPS group. Histopathological and immunohistochemical findings revealed that toll-like receptor 4 (TLR4) level and nuclear factor kappa B (NF-κB) expression increased in the LPS group compared to the Control group. In addition, the anti-Gram-negative activity showed a dose-dependent effect on Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa with the agar well diffusion method and the minimal inhibitory concentration (MIC). The MIC value was remarkable, especially on A. baumannii. We conclude that PGPE has the potential to generate desirable anti-bacterial and anti-inflammatory effects on LPS-induced acute kidney injury in rats.

Aquaporin-1 Facilitates Macrophage M1 Polarization by Enhancing Glycolysis Through the Activation of HIF1α in Lipopolysaccharide-Induced Acute Kidney Injury.

This study aimed to investigate how aquaporin 1 (AQP1) modulates hypoxia-inducible factor-1α (HIF1α) to promote glycolysis and drive the M1 polarization of macrophages. Within 12 h post-treatment with LPS to induce acute kidney injury in rats, a significant upregulation of AQP1 and HIF1α protein levels was noted in serum and kidney tissues. This elevation corresponded with a decrease in blood glucose concentrations and an enhancement of glycolytic activity relative to the control group. Furthermore, there was a pronounced reduction in the circulating levels of the anti-inflammatory cytokine IL-10, accompanied by an upregulation in the levels of the pro-inflammatory cytokines IL-6 and TNF-α. The administration of an HIF1α inhibitor reversed these effects, which did not affect the production of AQP1 protein. In cellular assays, AQP1 knockdown mitigated the increase in HIF1α expression induced by LPS. Furthermore, the suppression of HIF1α with PX-478 led to decreased expression levels of Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA), indicating that AQP1 regulates glycolysis through HIF1α. M1 polarization of macrophages was reduced by AQP1 knockdown and was further diminished by the addition of an HIF1α inhibitor. Inhibition of the glycolytic process not only weakened M1 polarization but also promoted M2 polarization, thereby reducing the release of inflammatory cytokines. These findings provide a novel perspective for developing therapeutic strategies that target AQP1 and HIF1α, potentially improving the treatment of sepsis-associated AKI.

Lactoferrin alleviates gentamicin-induced acute kidney injury in rats by suppressing ferroptosis: Highlight on ACSL4, SLC7A11, NCOA4, FSP1 pathways and miR-378a-3p, LINC00618 expression

The use of gentamicin (GNT) is associated with acute kidney injury (AKI). Ferroptosis is a newly recognized iron-dependent, non-apoptotic cell death that can lead to AKI. Lactoferrin (LF), an iron-binding glycoprotein, was previously reported to be renoprotective. Nonetheless, LF's impact on GNT-induced AKI and ferroptosis has not yet been investigated. Accordingly, we assessed the dose-dependent effect of LF on GNT-induced AKI and its influence on ferroptosis. Thirty-six male rats were allocated as control, LF, GNT (100 mg/kg/day, i.p.), and groups given LF (100, 200, and 300 mg/kg, p.o.) for 14 days prior concurrently with GNT (Day 8–14). The high dose of LF (300 mg/kg) showed better histopathological picture, higher creatinine clearance, reduced serum and urine levels of kidney injury markers when compared to the GNT group and the lower two doses. These nephroprotective effects of LF can be attributed to the observed reduction in renal ferrous iron, 4-HNE, and MDA, miR-378a-3p and ALOX15 expression, TFR1, NCOA4, and ACSL4 protein expression and the increased LINC00618 expression, GSH levels, GPX4, SLC7A11, and FSP1 protein expression. In conclusion, LF high dose was the most renoprotective against GNT-induced AKI, in which suppression of ferroptosis pathways was a likely contributor to its protective mechanism.

Protection Effect of Soy Isoflavones (Genistein and Daidzein) on Hematologic Parameters in Acute Kidney Injury

Background: Acute kidney injury (AKI) is a severe, high-morbidity condition with limited effective preventative and therapeutic strategies despite advancements in understanding and treatment. Specific Background: Rhabdomyolysis-induced acute kidney injury (AKI) presents significant challenges in renal research, but soy isoflavones, particularly GN and DZ, have shown potential in mitigating oxidative stress and inflammation. Knowledge Gap: Soy isoflavones, while potentially providing renal protection, their impact on renal and hematologic parameters in glycerol-induced AKI models has not been thoroughly studied. Aims: The study evaluated the effectiveness of soy isoflavones in regulating renal and hematologic parameters in a glycerol-induced AKI rat model, assessing their potential as therapeutic agents. Results: The study involving adult female Wistar rats showed that pretreatment with glycerol or dihydroxystilbene significantly reduced urinary β2-microglobulin, albumin, BUN, and serum creatinine levels in the AKI-induced group, reversing hematological changes. Novelty: The study explores the protective effects of soy isoflavones on renal function and hematologic parameters in AKI, highlighting GN's superior efficacy over DZ. Implications: Soy isoflavones, particularly GN, may be potential preventive or therapeutic strategies for AKI caused by rhabdomyolysis, warranting further research for clinical applications. Highlights: GN and DZ reduce kidney damage in glycerol-induced AKI. GN is more effective than DZ in kidney and blood parameters. Soy isoflavones could treat or prevent AKI. Keywords: Acute kidney injury, soy isoflavones, glycerol-induced AKI, renal protection, hematologic parameters

Hollow mesoporous Prussian blue nanoenzymes as Rapamycin carrier for targeted treatment of ischemia/reperfusion-induced acute kidney injury through pro-mitophagy and oxidative stress alleviation

The kidney’s abundant mitochondrial content and substantial oxygen requirements make it particularly vulnerable to a series of detrimental events following ischemia/reperfusion (I/R). These events encompass oxidative stress, mitochondrial impairment, depletion of adenosine triphosphate (ATP), and inflammation, cumulatively leading to acute kidney injury (AKI). Currently, no approved therapy beyond supportive care is available for AKI. While numerous studies have focused on neutralizing pre-existing reactive oxygen species (ROS) to mitigate AKI, insufficient attention has been paid to addressing the root causes of ROS. Here, we prepared Rapamycin (Rapa)-loaded hollow mesoporous Prussian blue nanoparticles (HMPB-Rapa) and grafted injured renal-targeted hyaluronic acid (HA) onto HMPB-Rapa (HA-HMPB-Rapa), which effectively scavenge pre-existing ROS and the source (massive damaged mitochondria) through the dual function of HMPB carrier and Rapa, thus preventing the further burst of ROS. In the I/R-induced AKI rat model, a single-dose of HA-HMPB-Rapa 6 h after I/R injury effectively inhibited oxidative stress and inflammation, protected renal cells from apoptotic damage, as well as ultimately restored renal function, and attenuated pathological changes. Mechanistically, HA-HMPB-Rapa cleared damaged mitochondria by activating the pro-mitophagy signaling pathway (PINK-1/Parkin-P62-LC3), cutting off the conduction in the intrinsic apoptotic pathway mediated by the Bax-Cyt-c-Cleaved Casp-3 signaling axis, and reduced the expression of renal tubular marker kidney injury molecule-1. HA-HMPB-Rapa represents an exciting new avenue for the treatment of diseases related to I/R-induced injury.

Renal Protective Effect of Umbelliferone on Acute Kidney Injury in Rats via Alteration of HO-1/Nrf2 and NF-κB Signaling Pathway.

Acute kidney injury (AKI), formerly known as acute renal failure, refers to a sudden and often reversible decline in kidney function. Inflammatory reaction and oxidative stress play a crucial role in the expansion of renal disease. In this experimental study, we scrutinized the renal protective effect of umbelliferone against gentamicin induced renal injury in the rats and explore the mechanism. Wistar rats were used in this study and Gentamicin was used for the induction the AKI in the rats and rats were received the oral administration of umbelliferone. The body weight, organ weight, renal, oxidative stress, cytokines, inflammatory parameters were estimated. The mRNA expression caspase-3, Bax, Bcl-2, TNF-α, IL-1β, IL-6, IL-10, HO-1, and Nrf2 were estimated. Umbelliferone remarkably improved the body weight and altered the absolute and relative weight of hepatic and renal tissue. Umbelliferone significantly suppressed the level of BUN, Scr, magnesium, calcium, phosphorus, sodium, and potassium along with altered the level of oxidative stress parameters like CAT, SOD, GSH, LPO, and GPx. Umbelliferone altered the level of cytokines viz., TNF-α, Il-1β, IL-6, IL-10; inflammatory parameters like PGE2, COX-2, TGF-β, NF-κB, respectively. Umbelliferone significantly altered the mRNA expression of caspase-3, Bax, Bcl-2, TNF-α, IL-1β, IL-6, IL-10, HO-1, and Nrf2. The result showed the renal protective effect of umbelliferone against gentamycin induced renal disease via alteration of HO-1/Nrf2 and NF-κB Signaling Pathway.

The Potential Renoprotective Effects of Ticagrelor in Rhabdomyolysis-Induced Acute Kidney Injury in Rat

The Potential Renoprotective Effects of Ticagrelor in Rhabdomyolysis-Induced Acute Kidney Injury in Rat

Loganin Ameliorates Acute Kidney Injury and Restores Tofacitinib Metabolism in Rats: Implications for Renal Protection and Drug Interaction.

Tofacitinib, a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, is metabolized through hepatic cytochrome P450 (CYP), specifically CYP3A1/2 and CYP2C11. Prolonged administration of rheumatoid arthritis medications is generally associated with an increased risk of renal toxicity. Loganin (LGN), an iridoid glycoside, has hepatorenal regenerative properties. This study investigates the potential of LGN to mitigate acute kidney injury (AKI) and its effects on the pharmacokinetics of tofacitinib in rats with cisplatin-induced AKI. Both intravenous and oral administration of tofacitinib to AKI rats significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) compared with control (CON) rats, an increase attributed to the decelerated non-renal clearance (CLNR) and renal clearance (CLR) of tofacitinib. Administration of LGN to AKI rats, however, protected kidneys from severe impairment, restoring the pharmacokinetic parameters (AUC, CLNR, and CLR) of tofacitinib to those observed in untreated CON rats, with partial recovery of kidney function, as evidenced by an increase in creatinine clearance (CLCR). Possible interactions between drugs and natural components should be considered, especially when co-administering both a drug and a natural extract containing LGN or iridoid glycosides to patients with kidney injury.

Screening for Early Biomarkers of Cisplatin-Induced Acute Kidney Injury in Rats Through Serum Metabolomics Technology.

To systematically identify early biomarkers of cisplatin-induced acute kidney injury (AKI) in rats. An experimental study. Place and Duration of the Study: Experimental Animal Laboratory of Lanzhou University, Gansu, China, and the Department of Pharmacy, The First Hospital of Lanzhou University, Gansu, China, from July 2022 to October 2023. In this study, an AKI model was established by continuously injecting cisplatin into rats at a dose of 1 mg/kg once a day for control group and for 2, 3, 4, and 5 days to other four groups, respectively. Subsequently, rat plasma samples were collected for metabolomics analysis to identify early differentiated metabolites in the plasma prior to creatinine elevation. Furthermore, accurate HPLC-MS/MS methods were developed to validate the biomarker variation in other AKI models. The occurrence of time-dependent renal cortical injury and significant alterations of creatinine (Cr) concentration were observed on day-4 and 5, which demonstrated successful model construction. Sixty-six compounds changed on Day-2 while 61 compounds changed on Day-3. Eleven compounds with variable importance in projection (VIP) >1.5 and false discover rate (FDR) <0.2 were selected and identified by HPLC-MS/MS. Among these, N-acetylglutamine and citramalic acid changed earlier than serum creatinine (sCr) in the AKI model. N-acetylglutamine and citramalic acid may serve as early biomarker of cisplatin-induced AKI. Acute kidney injury, Biomarker, Cisplatin, Metabolomics, LC-MS/MS, Rats.

Protective role of melatonin against diclofenac-induced acute kidney injury

Diclofenac (DF), a non-steroidal anti-inflammatory drug, is commonly used to relieve pain and inflammation. High doses of DF might induce acute kidney injury (AKI), particularly in elderly, a known vulnerable population. AimWe aimed to assess the protective role of melatonin (Mel) on DF-induced AKI in aged rats and to highlight the underpinning mechanisms include, oxidative stress and inflammation focusing on microRNA-34a (miR-34a), nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 (Nrf2/HO-1) and NLR family-pyrin domain containing-3 (NLRP3) inflammasome pathways, and to elucidate the possibility of epithelial sodium channel (ENaC) involvement. Materials and methodsThirty old male Wistar rats were allocated randomly into 3 groups: Control, DF and Mel-DF groups. Key findingsMelatonin provided nephroprotective effects against DF-induced AKI via attenuating the expression of renal miR-34a and subsequently promoting the signaling of Nrf2/HO-1 with elevation of the antioxidant defense capacity and suppressing NLRP3 inflammasomes. Melatonin alleviated DF-induced hypernatremia via decreasing the ENaC expression. Renal histopathological examination revealed significant reduction in vascular congestion, mononuclear infiltration, glomerulo-tubular damage, fibrosis and TNF-α optical density. SignificanceIt can be assumed that melatonin is a promising safe therapeutic agent in controlling DF-induced AKI in elderly.

Medicinal evaluation and molecular docking study of osajin as an anti-inflammatory, antioxidant, and antiapoptotic agent against sepsis-associated acute kidney injury in rats

Despite efforts to find effective drugs for sepsis-associated acute kidney injury (SA-AKI), mortality rates in patients with SA-AKI have not decreased. Our study evaluated the protective effects of isoflavone osajin (OSJ) on SA-AKI in rats by targeting inflammation, oxidative stress, and apoptosis, which represent the cornerstones in the pathophysiological mechanism of SA-AKI. Polymicrobial sepsis was induced in rats via the cecal ligation and puncture (CLP) technique. Markers of oxidative stress were evaluated in kidney tissues using biochemical methods. The expression of interleukin-33 (IL-33), 8-hydroxydeoxyguanosine (8-OHdG), caspase-3, and kidney injury molecule-1 (KIM-1) was evaluated as indicators of inflammation, DNA damage, apoptosis, and SA-AKI respectively in the kidney tissues using immunohistochemical and immunofluorescent detection methods. The CLP technique significantly (p < 0.001) increased lipid peroxidation (LPO) levels and significantly (p < 0.001) decreased the activities of superoxide dismutase and catalase in kidney tissues. In the renal tissues, strong expression of IL-33, 8-OHdG, caspase-3, and KIM-1 was observed with severe degeneration and necrosis in the tubular epithelium and intense interstitial nephritis. In contrast, the administration of OSJ significantly (p < 0.001) reduced the level of LPO, markedly improved biomarkers of antioxidant status, decreased the levels of serum creatinine and urea, lowered the expression of IL-33, 8-OHdG, caspase-3, and KIM-1 and alleviated changes in renal histopathology. A promising binding score was found via a molecular docking investigation of the OSJ-binding mode with mouse IL-33 (PDB Code: 5VI4). Therefore, OSJ protects against SA-AKI by suppressing the IL-33/LPO/8-OHdG/caspase-3 pathway and improving the antioxidant system.

Renoprotective effects of apocynin and/or umbelliferone against acrylamide-induced acute kidney injury in rats: role of the NLRP3 inflammasome and Nrf-2/HO-1 signaling pathways.

Acrylamide (ACR) is a toxic, probably carcinogenic compound commonly found in fried foods and used in the production of many industrial consumer products. ACR-induced acute kidney injury is mediated through several signals. In this research, we investigated, for the first time, the therapeutic effects of phytochemicals apocynin (APO) and/or umbelliferone (UMB) against ACR-induced nephrotoxicity in rats and emphasized the underlying molecular mechanism. To achieve this goal, five groups of rats were randomly assigned: the control group received vehicle (0.5% CMC; 1 ml/rat), ACR (40 mg/kg, i.p.), ACR + APO (100 mg/kg, P.O.), ACR + UMB (50 mg/kg, P.O.), and combination group for 10 days. In ACR-intoxicated rats, there was a significant reduction in weight gain while the levels of blood urea, uric acid, creatinine, and Kim-1 were elevated, indicating renal injury. Histopathological injury was also observed in the kidneys of ACR-intoxicated rats, confirming the biochemical data. Moreover, MDA, TNF-α, and IL-1β levels were raised; and GSH and SOD levels were decreased. In contrast, treatment with APO, UMB, and their combination significantly reduced the kidney function biomarkers, prevented tissue damage, and decreased inflammatory cytokines and MDA. Mechanistically, it suppressed the expression of NLRP-3, ASC, GSDMD, caspase-1, and IL-1β, while it upregulated Nrf-2 and HO-1 in the kidneys of ACR-intoxicated rats. In conclusion, APO, UMB, and their combination prevented ACR-induced nephrotoxicity in rats by attenuating oxidative injury and inflammation, suppressing NLRP-3 inflammasome signaling, enhancing antioxidants, and upregulating Nrf-2 and HO-1 in the kidneys of ACR-induced rats.

Sodium selenite attenuates inflammatory response and oxidative stress injury by regulating the Nrf2/ARE pathway in contrast-induced acute kidney injury in rats

BackgroundContrast-induced acute kidney injury (CI-AKI) is an acute renal complication that occurs after intravascular contrast agent administration. Sodium selenite (SS) is an inorganic source of Se and has potent antioxidant properties. This study intends to examine its anti-inflammatory and antioxidant effects in CI-AKI.MethodsA rat CI-AKI model was established with the pretreatment of SS (0.35 mg/kg). Hematoxylin-eosin staining was employed for histopathological analysis of rat kidney specimens. Biochemical analysis was conducted for renal function detection. Tissue levels of oxidative stress-related markers were estimated. Reverse transcription-quantitative polymerase chain reaction revealed the mRNA levels of proinflammatory cytokines. Western blotting showed the Nrf2 signaling-related protein expression in the rat kidney.ResultsSS administration alleviated the renal pathological changes and reduced the serum levels of serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin, cystatin C, and urinary level of kidney injury molecule-1 in CI-AKI rats. SS attenuated oxidative stress and inflammatory response in CI-AKI rat kidney tissues. SS activated the Nrf2 signaling transduction in the renal tissues of rats with CI-AKI.ConclusionSS ameliorates CI-AKI in rats by reducing oxidative stress and inflammation via the Nrf2 signaling.

Targeting Nrf2/HO-1 and NF-κB/TNF-α signaling pathways with empagliflozin protects against atrial fibrillation-induced acute kidney injury in rats

A bidirectional relationship exists between atrial fibrillation (AF) and kidney function. Uncontrolled AF may lead to kidney injury, whereas renal dysfunction may contribute to AF initiation and maintenance. This study aimed to investigate the protective effect of the sodium glucose cotransporter-2 inhibitor empagliflozin (EMPA) on acute kidney injury (AKI) associated with AF induced by acetylcholine and calcium chloride (ACh/CaCl2) in rats and elucidate the potential underlying mechanism. Rats were randomly divided as follows: control (CTRL) group: administered vehicles only; AF group: intravenously injected 1 ml/kg of an ACh/CaCl2 mixture for seven days to induce AF; EMPA group: orally administered EMPA (30 mg/kg) for seven days; AF+EMPA10 and AF+EMPA30 groups: co-administered the induction mixture and EMPA (10 and 30 mg/kg, respectively) for seven days. Our results showed that EMPA (10 and 30 mg/kg) effectively maintained kidney function and demonstrated a significant antioxidant potential. EMPA also suppressed AF-induced renal tubulointerstitial injury and fibrotic changes concurrently with reducing renal levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6, as well as the pro-fibrotic marker transforming growth factor beta-1 and collagen type I. Mechanistically, EMPA boosted nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) renal tissue expression while repressing nuclear factor kappa B (NF-κB) activation. In addition, these beneficial effects of EMPA on kidneys were concurrent with its ability to effectively inhibit AF-related electrocardiographic changes, reduce incidence and duration of AF episodes, and markedly suppress serum B-type natriuretic peptide and C-reactive protein levels. In conclusion, EMPA protected against AKI associated with AF induced by ACh/CaCl2 in rats through simultaneous modulation of the Nrf2/HO-1 and the NF-κB/TNF-α signaling pathways, exerting antioxidant, anti-inflammatory, and anti-fibrotic effects.

Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs

Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1β, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.

Protective effects of nodosin against lipopolysaccharide-induced acute kidney injury through regulation of oxidative stress, inflammation, and ferroptosis in rats.

This research aimed to explore the impact of nodosin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in rats. The study involved administering nodosin orally at doses of 2 and 4mg/kg body weight orally to rats for 7 days before induction of AKI. Toward the end of the study, urine, blood, and kidneys were gathered from the rats to undergo biochemical and molecular examination after sacrificing them. Serum Scr, BUN, urine NGAL, and KIM-1 levels were significantly decreased in nodosin-treated AKI rats. Besides, nodosin administration resulted in a significant reduction in kidney MDA and 4-HNE levels. In contrast, antioxidant enzymes such as SOD, CAT, GPx, and GST levels increased, as well as Nrf2, NQO1, and HO-1 levels increased, while Keap-1 mRNA levels decreased in AKI rats. In addition, AKI rats treated with nodosin reversed excessive ferroptosis in the kidneys of LPS-induced AKI rats, as evidenced by increased mRNA and protein levels of GPX4, SLC7A11, and FTH-1. The administration of nodosin significantly reduced levels of inflammatory markers including TLR4, MYD88, NF-κB p65, IkKβ, and IL-1β, while IL-10 levels increased in the AKI-induced rats. Besides, histopathological changes were reduced in AKI-induced rats treated with nodosin. Nodosin proves highly beneficial in safeguarding the kidney from AKI by regulating oxidative stress, inflammation, and ferroptosis. The treatment of AKI could greatly benefit from this option.

The renoprotective effect of Tibolone in sepsis-induced acute kidney injury.

Sepsis-induced acute kidney injury (AKI) remains a major challenge in intensive care, contributing significantly to morbidity and mortality. Tibolone, known for its neuroprotective and hormonal properties, has not been explored for its potential in AKI management. This study investigates the protective effects of Tibolone and its underlying mechanisms involving Sirtuin-1 (SIRT1) and Yes-Associated Protein (YAP) in a rat sepsis model. Thirty-six female Wistar albino rats underwent cecal ligation and puncture (CLP) to induce sepsis. They were randomly assigned to control, CLP+Saline, and CLP+Tibolone groups. Tibolone was administered intraperitoneally. Biomarkers, including Sirtuin (SIRT1), Yes-associated protein (YAP), Tumor necrosis factor (TNF-α), High mobility group box 1 (HMGB1), malondialdehyde (MDA), creatinine, and urea, were assessed. Histopathological examination evaluated renal damage. Tibolone administration significantly reduced plasma TNF-α, HMGB1, MDA, creatinine, and urea levels compared to the CLP+Saline group. Moreover, Tibolone elevated SIRT1 and YAP levels in kidney tissues. Histopathological examination demonstrated a significant decrease in tubular epithelial necrosis, luminal debris, dilatation, hemorrhage, and interstitial inflammation in Tibolone-treated rats. This study unveils the protective role of Tibolone against sepsis-induced AKI in rats. The improvements in inflammatory and oxidative biomarkers and histological evidence suggest Tibolone's potential as a therapeutic intervention in sepsis-associated kidney injury. The upregulation of SIRT1 and YAP indicates their involvement in Tibolone's renoprotective mechanisms. Further investigations are warranted to explore Tibolone's translational potential in human sepsis-induced AKI.