NGAL Levels Research Articles

Reno-protective potential of poncirin against polyethylene microplastics instigated kidney damage in rats via regulating Nrf-2/Keap-1 pathway

Polyethylene microplastics (PEMPs) are noxious environmental pollutants that are documented to cause organ damage including the kidneys. Poncirin (PON) is a naturally occurring flavonoid which demonstrates a wide range of pharmacological properties. This experiment was conducted to evaluate the palliative potential of PON against PEMPs by examining a range of biochemical and physiological parameters. Twenty-four male albino rats were randomly apportioned into four distinct groups including the control, PEMPs (1.5 mgkg−1), PEMPs (1.5 mgkg−1) + PON (20 mgkg−1) & only PON (20 mgkg−1). Our results displayed that PEMPs intoxication escalated the levels of urea, KIM-1, creatinine & NGAL while demising the creatinine clearance level. Besides reduction in the activities of GPx, GST, HO-1, CAT, GSR & upsurge in the levels of MDA and ROS were detected in PEMPs group. Conversely, the levels of inflammatory markers including COX-2, IL-1β, NF-kB and TNF-α were augmented following the PEMPs intoxication. Besides, the results of current research demonstrated that levels of Bax & caspase-3 were more than normal whereas the Bcl-2 expression was lowered from its standard value due to PEMPs provision. However, PON treatment significantly restored the PEMPs-induced biochemical impairments. Therefore, PON could be used as a therapeutic compound to ameliorate PEMPs-induced kidney impairments in rats, possibly due to its tremendous pharmacotherapeutic potential.

Protective effect of β-sitosterol against high-fructose diet-induced oxidative stress, and hepatorenal derangements in growing female sprague-dawley rats

BackgroundChronic consumption of a high-fructose diet causes oxidative stress that compromises kidney and liver health. β-sitosterol (Bst), a phytosterol, is a functional nutrient with health benefits. β-sitosterol antioxidant activity protects the liver and kidney from ROS-mediated damage and lipid peroxidation. We evaluated the potential renoprotective and hepatoprotective effects of orally administrated β-sitosterol in high-fructose diet-fed growing female rats. Thirty-five 21-day old female Sprague-Dawley rat pups were randomly assigned to and administered the following treatments for 12 weeks: group I- standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group II- SRC + 20% w/v fructose solution (FS) as drinking fluid + PC; group III- SRC + FS + 100 mg/kg body mass (BM) fenofibrate in gelatine cube; group IV- SRC + FS + 20 mg/kg BM β-sitosterol gelatine cube (Bst) and group V- SRC + PW + Bst. The rats were fasted overnight, weighed then euthanised. Blood was collected, centrifuged and plasma harvested. Livers and kidneys were excised, weighed and samples preserved for histological assessments. Plasma biomarkers of oxidative stress, liver and kidney function and renal tubular injury were assessed.ResultsHigh fructose diet fed rats had increased plasma KIM-1, NGAL (p < 0.001) and MDA levels (p < 0.05). Dietary fructose caused microvesicular and macrovesicular steatosis, and reduced glomerular density, Bowman’s capsule area and urinary space. β-sitosterol protected against the high-fructose diet-induced hepatic steatosis and glomerular disturbances without adverse effects on liver and kidney function.Conclusionsβ-sitosterol, as a dietary supplement, could potentially be exploited to prevent high-fructose diet-induced NAFLD and to protect against high-fructose diet-induced renal tubular injury.

The power of trans-sodium crocetinate: exploring its renoprotective effects in a rat model of colistin-induced nephrotoxicity.

Colistin, a multidrug-resistant gram-negative bacterial infection medication, has been associated with renal impairment and failure. Trans-sodium crocetinate (TSC), a saffron-derived chemical recognized for its antioxidant and nephroprotective properties, was studied in this study to determine its potential to alleviate the nephrotoxic effects of colistin. Forty-two male Wistar rats were randomly classified into seven groups (n = 6): (1) control (normal saline, 12 days, i.p.), (2) colistin (22 mg/kg, 7 days, i.p.), (3-5) colistin + TSC (25, 50, and 100 mg/kg, 12 days, i.p., starting from 5 days before colistin), (6) TSC (100 mg/kg, 12 days, i.p.), (7) colistin + vitamin E (100 IU/kg, 12 days, i.p). On day 13, the rats were euthanized and the serum content of creatinine, BUN, Na+, and K+, as well as oxidative stress (GSH, MDA, SOD, CAT), inflammatory (IL-1β), apoptotic (Bax, Bcl-2, caspase-3, 8, 9), and autophagy (Beclin-1, LC3) markers, NGAL, and histopathological changes in the kidney were measured. Colistin significantly increased serum creatinine, BUN, MDA, IL-1β, caspase-3,8,9, Bax, Beclin-1, LC3, and NGAL levels in kidney tissue. It also caused inflammation, focal necrosis of tubular epithelial cells, protein cast, and acute tubular necrosis. Furthermore, colistin decreased SOD, CAT, GSH, and Bcl-2 levels. TSC and vitamin E administration along with colistin restored most of the alterations induced by colistin. Overall, it could be concluded that colistin induces oxidative stress, inflammation, autophagy, and apoptosis, which can cause kidney injury. However, TSC can also be used as a therapeutic agent to reduce injuries caused by colistin.

Potential effects of Resatorvid and alpha lipoic acid on gentamicin-induced nephrotoxicity in rats.

Gentamicin is an aminoglycoside antibiotic with a rapid bactericidal effect on the treatment of many infections. However, its use at high concentrations for more than 7 days causes nephrotoxic side effects. This study investigated the potential of Resatorvid and alpha lipoic acid (ALA) in mitigating gentamicin-induced nephrotoxicity in rats, considering biochemical, histopathological, and molecular parameters. This study randomly distributed 34 Wistar albino rats into four groups: healthy control (n = 6), Gentamicin (80 mg/kg, n = 7), Gentamicin + Sham (%10 hydroalcoholic solution, n = 7), Gentamicin + Resatorvid (5 mg/kg, n = 7), and Gentamicin + ALA (100 mg/kg, n = 7). Resatorvid treatment led to a statistically significant decrease in urinary IL-18, KIM-1, and NGAL levels, whereas ALA treatment significantly reduced KIM-1 levels compared to the gentamicin-only group. Both Resatorvid and ALA showed partial reductions in urine creatinine levels. Moreover, treatments with Resatorvid and ALA resulted in statistically significant decreases in NRF-2, CAS-3, and NR4A2 expressions. However, only Resatorvid demonstrated a statistically significant decrease in NF-B expression. These findings highlight the potential of Resatorvid in ameliorating gentamicin-induced nephrotoxicity, thereby expanding the therapeutic utility of gentamicin and enhancing its efficacy against infections.

Diagnostic efficacy of urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 for early detection of acute kidney injury in dogs with leptospirosis or babesiosis.

This study evaluates the diagnostic efficacy of urinary biomarkers, Neutrophil Gelatinase-Associated Lipocalin (uNGAL), and Kidney Injury Molecule-1 (uKIM-1), in identifying Acute Kidney Injury (AKI) in dogs affected with leptospirosis or babesiosis. Acute kidney injury was diagnosed based on the increase in serum creatinine levels above 0.3mg/dL within 48h and dogs were categorized according to AKI grades based on International Renal Interest Society guidelines. Traditional biomarkers (serum creatinine and blood urea nitrogen) and novel biomarkers like urinary NGAL and urinary KIM-1 levels were measured and compared to concentrations obtained in control dogs. Statistical analysis assessed significant differences (P < 0.01) across AKI grades, specifically noting elevated urinary NGAL and KIM-1 in IRIS grade I AKI (P < 0.001). The study highlights the diagnostic significance of urinary NGAL and KIM-1 as early indicators of renal damage, particularly valuable in non-azotemic AKI cases, offering promising markers for early AKI diagnosis in veterinary clinical settings. These biomarkers demonstrate clinical utility and underscore their potential for improving AKI management in veterinary medicine. Further validation studies involving larger cohorts and diverse etiologies of AKI are needed to confirm the diagnostic accuracy and clinical utility of urinary NGAL and KIM-1 in veterinary practice.

The protective effect of bergamot polyphenolic fraction on reno-cardiac damage induced by DOCA-salt and unilateral renal artery ligation in rats

Abstract Funding Acknowledgements None. The complex pathological interactions between renal and cardiovascular systems represent a real global epidemic and renovascular hypertension remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of citrus bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation (RAL). Adult male Wistar rats underwent unilateral renal artery ligation and treatment with 20 mg/kg deoxycorticosterone acetate (DOCA), twice a week for a period of 4 weeks, and 1% sodium chloride water. A subgroup of hypertensive rats received 100 mg/kg/day of BPF for 28 days, by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (CTRL). RAL DOCA-Salt rats showed a significant increase in mean arterial blood pressure (MAP; p&amp;lt;0.05 vs CTRL) which strongly increased the resistive index (RI; p&amp;lt;0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p&amp;lt;0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion, as shown by the increased time-to-peak (T2P; p&amp;lt;0.05) and the decreased whole peak capacity (Pk; p&amp;lt;0.01) in displacement and strain rate (p&amp;lt;0.05) in longitudinal motion. The hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) (p&amp;lt;0.05 in displacement and p&amp;lt;0.01 in strain rate vs CTRL). A significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p&amp;lt;0.05 for IL-12(40), p&amp;lt;0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p&amp;lt;0.001) was observed.This pathological condition was prevented by BPF treatment, by reducing the increase of blood pressure in RAL DOCA-Salt rats (p&amp;lt;0.05) and exerting a protective effect on the volume of the contralateral kidney (p&amp;lt;0.01). BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p&amp;lt;0.01) and reducing the T2P in strain rate motion (p&amp;lt;0.05). These effects significantly improve MOWD (p&amp;lt;0.05) preventing the overt dyssynchrony in cardiac wall motion. The reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of the pro-inflammatory cytokines and chemokines (p&amp;lt;0.05 for KC and IL-12(40), p&amp;lt;0.01 for GM-CSF, IL-13, and TNF- α)restoring physiological levels of NGAL (p&amp;lt;0.05) protein of the tethered kidney. In conclusion, the present results show that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage, suggesting the potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome.

#1110 The AHR antagonist CH223191 alleviates kidney injury and renal fibrosis in adenine-induced chronic kidney disease

Abstract Background and Aims The aryl hydrocarbon receptor (AhR) is a transcription factor that can be activated by a variety of endogenous and exogenous ligands, and is involved in varieties of biological processes. It has been confirmed that the expression of AhR in kidney is elevated in chronic kidney disease (CKD). However, the specific role of AhR signaling pathway in CKD and its molecular mechanism remain unclear. This study aims to investigate the role and underlying mechanism of AhR in CKD, providing potential targets for the treatment of CKD. Method Male C57/B6L mice were randomly divided into control group, model group and treatment group. The model group was fed 0.2% adenine diet for 14 days to establish CKD model, while the treatment group was treated with AhR antagonist CH223191. AhR agonist kynurenine and antagonist CH223191 was applied in mouse tubular epithelial (TCMK-1) cells to investigate the underlying mechanisms of AhR in vitro. The renal function, histological changes and renal fibrosis in mice were evaluated to explore the role of AhR in adenine-induced CKD. Histological changes were evaluated by PAS and MASSON stainings, immunohistochemistry and immunofluorescence. Western blot and qPCR were used to measure protein/gene transcription levels. Results The levels of serum creatinine (p &amp;lt; 0.0001) and urea nitrogen (p &amp;lt; 0.0001) in the model group were significantly increased, with obvious renal tubule dilation and renal fibrosis by PAS and MASSON staining. CH223191 treatment significantly reduced serum creatinine (p=0.0012) and urea nitrogen ( &amp;lt; 0.0001) levels in mice, and alleviated renal fibrosis histologically. Q-PCR and Western-Blot results showed that the renal expression level of AhR in the treatment group was decreased, while the expression levels of fibronectin (Fn) (p &amp;lt; 0.0001), α-smooth muscle actin (α-SMA) (p &amp;lt; 0.0001), type I collagen (p=0.0007) and transforming growth factor-β (TGF-b) (p=0.0027) were significantly decreased. In addition, the expression levels of N-GAL (p &amp;lt; 0.0001) and KIM-1 ( &amp;lt; 0.0001) molecular markers associated with kidney injury were reduced, suggesting that inhibiting AhR expression in vivo can reduce adenine-mediated kidney injury and renal fibrosis in CKD. In vitro experiments indicated that kynurenic acid could induce the expression of AhR and AhR downstream regulatory gene CYP1b1 and upregulated fibrosis-related genes in tubular epithelial cells, while CH223191 treatment downregulated the fibrosis-related genes in tubular epithelial cells. Conclusion AhR mediates renal injury and renal fibrosis in adenine-induced CKD mice. AhR antagonist CH223191 exerts a renal protective effect by reducing the expression of AhR in renal tubular epithelial cells, thereby alleviating renal injury and renal fibrosis.

Plasma proenkephalin andneutrophil gelatinase-associated lipocalin predict mortality in ICU patients with acute kidney injury.

Acute kidney injury (AKI) is a common complication in patients admitted to intensive care unit (ICU) and mortality rates for this condition are high. To reduce the high incidence of short-term mortality, reliable prognostic indicators are required to facilitate early diagnosis and treatment of AKI. We assessed the ability of plasma proenkephalin (p‑PENK) and plasma neutrophil gelatinase-associated lipocalin (p‑NGAL) to predict 28-day mortality in AKI patients in intensive care. This prospective study, carried out between January 2019 and December 2019, comprised 150 patients (100 male) diagnosed with AKI after excluding 20 patients discharged within 24 h and those with missing hospitalization data. Blood samples were collected to determine admission p-PENK and p-NGAL levels. The study outcome was 28‑day mortality. The mean patient age was 68 years (female, 33%). The average P‑PENK and p‑NGAL levels were 0.24 ng/µL and 223.70 ng/mL, respectively. P‑PENK levels >0.36 ng/µL and p‑NGAL levels >230.30 ng/mL were used as critical values to reliably indicate 28‑day mortality for patients with AKI (adjusted hazard ratios 0.785 [95% confidence interval 0.706-0.865, P<0.001] and 0.700 [95% confidence interval 0.611-0.789, P<0.001], respectively). This association was significant for mortality in patients in intensive care with AKI. Baseline p-PENK (0.36 ng/µL) and p-NGAL (230.30 ng/mL) levels and their respective cut-off values showed clinical value in predicting 28-day mortality. Serum PENK and NGAL levels, when used in conjunction, improved the accuracy of predicting 28-day mortality in patients with AKI while retaining sensitivity and specificity.

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.

Therapeutic potential of Lactobacillus casei and Chlorella vulgaris in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD)-associated kidney damages: a stereological study.

The non-alcoholic fatty liver disease (NAFLD) is prevalent in as many as 25% of adults who are afflicted with metabolic syndrome. Oxidative stress plays a significant role in the pathophysiology of hepatic and renal injury associated with NAFLD. Therefore, probiotics such as Lactobacillus casei (LBC) and the microalga Chlorella vulgaris (CV) may be beneficial in alleviating kidney injury related to NAFLD. This animal study utilized 30 C57BL/6 mice, which were evenly distributed into five groups: the control group, the NAFLD group, the NAFLD + CV group, the NAFLD + LBC group, and the NAFLD + CV + LBC group. A high-fat diet (HFD) was administered to induce NAFLD for six weeks. The treatments with CV and LBC were continued for an additional 35 days. Biochemical parameters, total antioxidant capacity (TAC), and the expression of kidney damage marker genes (KIM 1 and NGAL) in serum and kidney tissue were determined, respectively. A stereological analysis was conducted to observe the structural changes in kidney tissues. A liver histopathological examination confirmed the successful induction of NAFLD. Biochemical investigations revealed that the NAFLD group exhibited increased ALT and AST levels, significantly reduced in the therapy groups (p < 0.001). The gene expression levels of KIM-1 and NGAL were elevated in NAFLD but were significantly reduced by CV and LBC therapies (p < 0.001). Stereological examinations revealed reduced kidney size, volume, and tissue composition in the NAFLD group, with significant improvements observed in the treated groups (p < 0.001). This study highlights the potential therapeutic efficacy of C. vulgaris and L. casei in mitigating kidney damage caused by NAFLD. These findings provide valuable insights for developing novel treatment approaches for managing NAFLD and its associated complications.

Delivery of Mesenchymal Stem Cells during Hypothermic Machine Perfusion in a Translational Kidney Perfusion Study.

In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly into an organ without affecting the recipient. MSCs are multipotent, self-renewing cells with tissue-repair capacities, and their application to ameliorate ischemia- reperfusion injury (IRI) is being investigated in several preclinical and clinical studies. The aim of this study was to introduce MSCs into a translational model of hypothermic machine perfusion and to test the efficiency and feasibility of this method. Methods: three rodent kidneys, six porcine kidneys and three human kidneys underwent HMP with 1-5 × 106 labelled MSCs within respective perfusates. Only porcine kidneys were compared to a control group of 6 kidneys undergoing HMP without MSCs, followed by mimicked reperfusion with whole blood at 37 °C for 2 h for all 12 kidneys. Reperfusion perfusate samples were analyzed for levels of NGAL and IL-β by ELISA. Functional parameters, including urinary output, oxygen consumption and creatinine clearance, were compared and found to be similar between the MSC treatment group and the control group in the porcine model. IL-1β levels were higher in perfusate and urine samples in the MSC group, with a median of 285.3 ng/mL (IQR 224.3-407.8 ng/mL) vs. 209.2 ng/mL (IQR 174.9-220.1), p = 0.51 and 105.3 ng/mL (IQR 71.03-164.7 ng/mL) vs. 307.7 ng/mL (IQR 190.9-349.6 ng/mL), p = 0.16, respectively. MSCs could be traced within the kidneys in all models using widefield microscopy after HMP. The application of Mesenchymal Stem Cells in an ex vivo hypothermic machine perfusion setting is feasible, and MSCs can be delivered into the kidney grafts during HMP. Functional parameters during mimicked reperfusion were not altered in treated kidney grafts. Changes in levels of IL-1β suggest that MSCs might have an effect on the kidney grafts, and whether this leads to a positive or a negative outcome on IRI in transplantation needs to be determined in further experiments.

Interleukin-6/Glycoprotein130 Signaling Inhibition Ameliorates Renal Mitochondrial Dysfunction And Associated Renal Injury In Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and polycystic ovaries. Renal injury, increased central adiposity, and chronic low-grade systemic inflammation are common characteristics of PCOS. Renal inflammation can induce mitochondrial dysfunction, which plays a pivotal role in renal pathophysiology and chronic kidney disease progression. Interleukin-6 (IL-6) is a key inflammatory cytokine that is involved in renal injury progression by activating its soluble receptor (sIL-6R) and a membrane-bound glycoprotein130 (gp130). Serum IL-6 levels are elevated in women with PCOS; however, its role in inducing renal mitochondrial dysfunction and consequently PCOS-mediated renal injury is unknown. Therefore, we aimed to test the hypothesis that hyperandrogenemia increases systemic and renal IL-6 levels, leading to the activation of IL-6/gp130 signaling, which in turn triggers intrarenal mitochondrial dysfunction and renal injury in a well-characterized mouse model of PCOS. Methods: Three-week-old peripubertal female mice were implanted with Silastic tubes filled with the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle for 12 weeks. Eight weeks post-Silastic tubes implantation, the animals were treated with the IL-6/gp130 signaling inhibitor SC144 (10 mg/kg, SC, 3x/week) or its vehicle for 4 weeks. Body weight (gravimetry), fat mass (EchoMRI), kidney weight (gravimetry), serum IL-6 (Bioplex), glomerular filtration rate (GFR, transcutaneous fluorescence), as well as the renal injury markers urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer), and NGAL (ELISA) were assessed. Renal gp130 protein and IL-6 mRNA expression were quantified by Western blot and RT-qPCR, respectively. The mitochondrial markers cytochrome C, succinate dehydrogenase A (SDHA), the mitochondrial stress protein HSP60, and voltage-dependent anion channel (VDAC) were assessed in the renal tissue by Western blot. H&amp;E stained renal sections were used for histopathological analysis. Freshly isolated kidney mitochondria were used to measure mitochondrial reactive oxygen species (mtROS) by Amplex Red assay. Moreover, mitochondrial complex I and complex II-driven respiration along with complex IV activity were assessed using Oroboros Fluorespirometer. Results: DHT significantly (p&lt;0.05) increased body weight (26.2±0.9 vs. 22.23±0.4 g), fat mass (3.2±0.4 vs. 1.9±0.4 g), kidney weight (365.6 ± 13.1 vs. 257.1 ± 3.7 mg), UACR (1,227±420 vs. 404±169 μg albumin/mg creatinine), urinary NGAL (2-fold), and serum IL-6 levels (2.2-fold). Additionally, DHT increased the expression of renal gp130 and IL-6 (1.5-fold) and decreased GFR (1067.2 ± 59.9 vs. 1335.6 ± 60.3 uL/min/100g body weight). Moreover, cytochrome c levels in PCOS mice were significantly lower (32%), while HSP60 levels were higher (4-fold). The latter changes were associated with higher mtROS generation (2-fold), as well as lower complexes I, II, III, and IV respiration (43-71%). PCOS mice also showed a worsen renal histological structure with congested glomeruli, exfoliation of luminal epithelial lining, and interstitial hemorrhage. SC144 therapy had no effect on kidney weight or GFR; however, it abolished DHT-induced increases in body weight and fat mass. Excitingly, SC144 treatment normalized the levels of UACR, and decreased both glomerular and tubular injury in PCOS mice. It also decreased renal HSP60 levels and mtROS generation and increased complex IV derived respiration. Conclusion and significance: Our findings suggest that IL-6/gp130 activation plays a significant role in renal outcomes in PCOS. Targeting IL-6 signaling could be a novel therapeutic approach to ameliorate renal injury in PCOS women. Supported by NIH grants NIGMS P20GM121334 to KSE, LLYC, and DGR; NIH-NIGMS P30GM149404 to SR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The impact of renal tubulointerstitial dysfunction on the early and long-term prognosis in chronic heart failure patients with preserved left ventricular ejection fraction

Aim. To study the dependence of the early-term (1 year) and long-term (5 years) prognosis in patients with chronic heart failure (CHF) of ischemic origin with preserved left ventricular ejection fraction (LVEF) depending on renal tubulointerstitial functional disorders. Materials and methods. The study involved 88 patients (men – 46.6 % (n = 41); women – 53.4 % (n = 47)) with CHF of ischemic origin, stage II A–B, stage II–IV according to NYHA, 67 % (n = 59) with sinus rhythm, and 33 % (n = 29) with atrial fibrillation. Patients with sinus rhythm and atrial fibrillation were matched in age (p = 0.483), height (p = 0.345), weight (p = 0.317), body surface area (p = 0.153). NGAL levels were analyzed using an ELISA kit (E-EL-H0096, Elabscience, USA). NAG levels were analyzed using an ELISA kit (SEA 069 Hu, Cloud-Clone Corp., USA). KIM-1 levels were analyzed using an ELISA kit (SEA 785 Hu, Cloud-Clone Corp., USA). Kaplan–Meier curves and Cox proportional hazards regression analysis were performed. Results. No significant difference was found in the frequency of the cumulative endpoint during the first-year follow-up from the initial level of two markers of tubulointerstitial injury – KIM-1 (Log-Rank Test: p = 0.57529) and NAG (Log-Rank Test: p = 0.86001). According to the results of analysis of the Cox proportional hazards, only a tendency to increase in the risk factors of adverse events were observed in case of elevated KIM-1 (HR = 1.66; p = 0.5795) and NAG levels (HR = 1.1712; p = 0.8626) in this CHF patients’ cohort. Kaplan–Meier analysis revealed a probable (Log-Rank Test; p = 0.00141) increase in the frequency of the cumulative endpoint during the first year of follow-up in CHF patients with preserved LVEF due to increased serum NGAL level more than 168 ng/ml. According to the univariate model, an elevated serum NGAL level is associated with an increase in the relative risk by 4.2 times (95 % CI 1.78–16.89; p = 0.014). A reduced sodium level less than 142.5 mmol/l was associated with an increase in number of adverse cardiovascular events during the first-year follow- ups by 22 % (HR = 1.22, p = 0.029). After 5 years of follow-up, a decrease in sodium level less than 142.3 mmol/l is also characterized by a probable difference of the cumulative Kaplan–Meier’s curves (Cox–Mantel F-Test, p = 0.00287). According to the univariate model of Cox proportional hazards, the relative risk of adverse cardiovascular events in patients with CHF during the 5-year follow-up has a tendency to increase by 1.04 times (95 % CI 0.85–1.27; p = 0.72). Serum NGAL, a marker of renal tubulo-interstitial injury, doesn’t lose its properties as a powerful marker of an unfavorable long-term prognosis in patients with CHF with preserved LVEF (HR = 5.96; 95 % CI 1.17–30.50; p = 0.032). Conclusions. The most powerful factors of the early (1-year) prognosis of adverse cardiovascular events in CHF patients with preserved left ventricular ejection fraction are the marker of tubulointerstitial injury, serum NGAL over 168 ng/ml, as well as the marker of tubulointerstitial dysfunction – the serum sodium level less than 142.5 mmol/l. The electrolyte imbalance, decreased sodium level less than 142.3 mmol/l, remains a powerful marker of an unfavorable long-term 5-year prognosis in CHF patients with preserved left ventricular ejection fraction, meanwhile serum NGAL, a marker of renal tubulointerstitial injury, besides doesn’t lose its prognostic value (HR = 5.96; 95 % CI 1.17–30.50; p = 0.032), but also is independent from the parameters of the age (p = 0.409) and gender (p = 0.397) in such patients.

Renoprotective effect of diacetylrhein on diclofenac-induced acute kidney injury in rats via modulating Nrf2/NF-κB/NLRP3/GSDMD signaling pathways

Diclofenac (DF)-induced acute kidney injury (AKI) is characterized by glomerular dysfunction and acute tubular necrosis. Due to limited treatment approaches, effective and safe drug therapy to protect against such AKI is still needed. Diacetylrhein (DAR), an anthraquinone derivative, has different antioxidant and anti-inflammatory properties. Therefore, the aim of the current study was to investigate the renoprotective effect of DAR on DF-induced AKI while elucidating the potential underlying mechanism. Our results showed that DAR (50 and 100 mg/kg) markedly abrogated DF-induced kidney dysfunction decreasing SCr, BUN, serum NGAL, and serum KIM1 levels. Moreover, DAR treatment remarkably maintained renal redox balance and reduced the levels of pro-inflammatory biomarkers in the kidney. Mechanistically, DAR boosted Nrf2/HO-1 antioxidant and anti-inflammatory response in the kidney while suppressing renal TLR4/NF-κB and NLRP3/caspase-1 inflammatory signaling pathways. In addition, DAR markedly inhibited renal pyroptosis via targeting of GSDMD activation. Collectively, this study confirmed that the interplay between Nrf2/HO-1 and TLR4/NF-κB/NLRP3/Caspase-1 signaling pathways and pyroptotic cell death mediates DF-induced AKI and reported that DAR has a dose-dependent renoprotective effect on DF-induced AKI in rats. This effect is due to powerful antioxidant, anti-inflammatory, and anti-pyroptotic activities that could provide a promising treatment approach to protect against DF-induced AKI.

Acute Kidney Injury Prediction Model Using Cystatin-C, Beta-2 Microglobulin, and Neutrophil Gelatinase-Associated Lipocalin Biomarker in Sepsis Patients.

AKI is a frequent complication in sepsis patients and is estimated to occur in almost half of patients with severe sepsis. However, there is currently no effective therapy for AKI in sepsis. Therefore, the therapeutic approach is focused on prevention. Based on this, there is an opportunity to examine a panel of biomarker models for predicting AKI. This prospective cohort study analysed the differences in Cystatin C, Beta-2 Microglobulin, and NGAL levels in sepsis patients with AKI and sepsis patients without AKI. The biomarker modelling of AKI prediction was done using machine learning, namely Orange Data Mining. In this study, 130 samples were analysed by machine learning. The parameters used to obtain the biomarker panel were 23 laboratory examination parameters. This study used SVM and the Naïve Bayes model of machine learning. The SVM model's sensitivity, specificity, NPV, and PPV were 50%, 94.4%, 71.4%, and 87.5%, respectively. For the Naïve Bayes model, the sensitivity, specificity, NPV, and PPV were 83.3%, 77.8%, 87.5%, and 71.4%, respectively. This study's SVM machine learning model has higher AUC and specificity but lower sensitivity. The Naïve Bayes model had better sensitivity; it can be used to predict AKI in sepsis patients. The Naïve Bayes machine learning model in this study is useful for predicting AKI in sepsis patients.

Longitudinal NGAL and cystatin C plasma profiles present a high level of heterogeneity in a mixed ICU population

BackgroundNGAL and Cystatin C (CysC) as biomarkers for the early detection of AKI are subject to both pathophysiological, as well as patient related heterogeneity. The aim of this study was to investigate the timeline of plasma levels of NGAL and CysC during the first seven days of ICU admission in a mixed ICU population and to relate these to AKI severity during ICU stay. Via these means we aimed to bring clarity to the previously reported heterogeneity of these renal biomarkers.MethodsProspective Observation Cohort. Consecutive patients admitted to adult ICU at an academic hospital in the Netherlands between 18-02-2014 and 31-03-2014 were included. Urine output, serum creatinine, plasma NGAL and CysC were recorded during the first seven days of ICU admission. Biomarker expression was analyzed based on KDIGO score and time of AKI diagnosis.Results335 patients were included, 110 met KDIGO criteria for AKI. NGAL and CysC plasma levels were higher in AKI patients compared to non-AKI, high variability in individual values resulted in 56% of AKI patients having a false negative, and 32% of non-AKI patients having a false positive. Individual biomarker levels were variable, and no pattern based on KDIGO score was observed.ConclusionsPlasma NGAL and CysC as biomarkers for the early AKI detection may be subject to pathophysiological, and patient related heterogeneity. Further understanding of individual biomarker profiles may help in their application amongst mixed ICU populations.Trial RegistrationThe need for informed consent was waived by the Institutional Ethical Review Board of the University Medical Center Groningen (METc 2013 − 174) by Prof. dr. W.A. Kamps on May 17th 2013.

Improvement of renal functions in mice with septic acute kidney injury using secretome of mesenchymal stem cells

BackgroundA potentially fatal complication of sepsis is septic acute kidney injury. Stem cell therapy is a potential new method of treating sepsis and has been applied to treat some human diseases. ObjectivesThis study investigated the effects of secretome-MSCs on NGAL, CRP, NF-κB, and MMP-9 proteins, and histopathology in mice with septic AKI. MethodsA post-test-only group design was conducted in 30 Balb/C male mice, which were randomly assigned to five groups: the control group was intraperitoneally injected with 0.5 ml of 0.9 % NaCl, the septic AKI, and the treatment groups (T1, T2, and T3) were intraperitoneally injected with 0.5 ml of 0.9 % NaCl and 0.3 mg/kg BW LPS single dose for three days. Three-day treatments of 150, 300, and 600 µl secretome-MSCs were administered intraperitoneally into the treatment groups. Furthermore, kidney and blood samples were collected for biochemical and histopathological analyses. ResultsThe T1, T2, and T3 groups had lower expression of NF-κB and MMP-9 and significantly lower CRP and NGAL levels than that of septic AKI group. T1 (1.21 ± 0.19), T2 (0.75 ± 0.22), and T3 (0.38 ± 0.14) groups demonstrated lower average scores for inflammation, necrosis, hemorrhage, and degeneration compared to septic AKI group (2.17 ± 0.13). ConclusionsAdministration of 600 µl/20 g BW secretome-MSCs suppresses NF-κB and MMP-9 expression and reduces CRP and NGAL levels. Meanwhile, the 150 and 300 µl/20 g BW doses also indicated a greater improvement in renal tissue damage of mice with septic AKI.

THE COMPREHENSIVE SYSTEMATIC REVIEW OF NEUTROPHIL GELATINASE–ASSOCIATED LIPOCALIN AS A PREDICTOR OF PRE-ECLAMPSIA

Background: The use of NGAL for preeclampsia and eclampsia prediction looks appealing, but one has to understand that NGAL levels increase in the state of inflammatory conditions associated with epithelial cell injury like pelvic inflammatory disease, chronic obstructive pulmonary disease, malignancies of breast, lungs, and colon. NGAL is also released from maternalfetal interface and is thought to be released when there is uterine vasoconstriction as happens in preeclampsia. The aim: This study aims to show about the comprehensive of neutrophil gelatinase-associated lipocalin as a peredictor of pre-eclampsia. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 143 articles, whereas the results of our search on SagePub brought up 24 articles. The results of the search conducted for the last year of 2014 yielded a total 70 articles for PubMed and 15 articles for SagePub. The result from title screening, a total 10 articles for PubMed and 12 articles for SagePub. In the end, we compiled a total of 8 papers. We included five research that met the criteria. Conclusion: The utility of NGAL for diagnosing and assessing the severity of preeclampsia. The increase in NGAL due to preeclampsia is attributed to the presence of endothelium dysfunction and systemic inflammation.

Astragaloside Ⅳ negatively regulates Gpr97-TPL2 signaling to protect against hyperhomocysteine-exacerbated sepsis associated acute kidney injury

BackgroundHyperhomocysteine (HHcy) plays an important role in promoting inflammation and cell death of tubular epithelial cells. However, the role of HHcy and Astragaloside IV (AS-IV) in sepsis associated acute kidney injury (S-AKI) remain unclear. PurposeA significant aspect of this study aimed to elucidate the effect of AS-Ⅳ treatment on HHcy-exacerbated S-AKI and reveal its potential mechanism. MethodsMale C57BL/6 J mice fed with specific diet containing 2% methionine were established as in vivo models, and AS-Ⅳ was orally administrated continuously for 3 weeks, and then LPS (10 mg·kg−1 bodyweight) was given by a single intraperitoneal injection. The renal morphological changes were evaluated by HE and PAS staining. RNA-sequencing analysis was applied to select key signaling. The NRK-52E cells exposed to Hcy or combined with LPS were used as in vitro models. The mRNA and protein expression levels of Gpr97-TPL2 signaling were examined by qRT-PCR and western blotting assays. ResultsIn vivo, HHcy mice developed more severe renal injury and prevalent tubular inflammation after LPS injection. In vitro, the levels of NGAL, Gpr97 and TPL2 were significantly increased in NRK-52E cells induced by Hcy (1.6 mM) or in combination with LPS. Notably, the effects of Hcy on TPL2 signaling was abolished by transfecting TPL2 siRNA or treating TPL2 inhibitor, without alterations in Gpr97. However, the enhancement of Gpr97-TPL2 signaling induced by Hcy was counteracted by Gpr97 siRNA. Subsequently, our findings demonstrated that AS-Ⅳ treatment can improve renal function in HHcy-exacerbated S-AKI mice. Mechanistically, AS-Ⅳ alleviated renal tubular damage characterized by abnormal increases in KIM-1, NGAL, TPL2, Gpr97, Sema3A and TNF-α, and decreases in survivin in vivo and in vitro mainly through suppressing the activation of Gpr97-TPL2 signaling. ConclusionThe present study suggested that HHcy-exacerbated S-AKI was mediated mechanically by activation of Gpr97-TPL2 signaling for the first time. Furthermore, our research also illustrated that AS-Ⅳ protected against HHcy-exacerbated S-AKI by attenuating renal tubular epithelial cells damage through negatively regulating Gpr97-TPL2 signaling, proposing a natural product treatment strategy for HHcy-exacerbated S-AKI.

Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of ATF4 and XBP1 genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.