Renal Protective Effects Research Articles

Artesunate-Nanoliposome-TPP, a Novel Drug Delivery System That Targets the Mitochondria, Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Oxidative Stress and Inflammatory Effects.

Acute kidney injury (AKI) is a syndrome, posing a substantial healthcare burden. The pathological basis of AKI is associated with inflammation and oxidative stress which cause additional damage to mitochondria. Artesunate (ATS) is a derivative of artemisinin isolated from Artemisia annua L. that is an effective treatment for malaria and favored for the prevention and treatment of kidney diseases. However, there are still challenges related to its efficacy, including poor water solubility, limited oral bioavailability and short half-life. Liposome-based nanoparticles are used for drug delivery due to their ideal biocompatibility and their ability to improve the bioavailability of specific drugs and enhance drug efficacy. In this study, a novel TPP-based natural ATS-nanoliposome, namely T-A-Ls, was applied for the treatment of AKI. ATS was encapsulated with or without triphenylphosphonium (TPP)-modified nanoliposomes. AKI was induced by cisplatin in C57BL/6J mice and a cisplatin-induced injury model was generated in HK-2 cells in vitro. Blood urea nitrogen (BUN), serum creatinine (Scr) measurements and section staining were utilized to assess renal protective effect of T-A-Ls. Inflammatory-related factors and proteins were quantified via Elisa, Immunofluorescence and Western Blot (WB). The anti-mitochondrial oxidative stress effect of T-A-Ls was determined by ROS, JC-1 and oxygen consumption rate (OCR) kits. Immunohistochemistry and WB were conducted to measure associated protein expressions. In vivo biodistribution and the concentration of T-A-Ls in kidney were also explored. T-A-Ls exhibited good oxidative resistance, preferential renal uptake, mitochondrial targeting, and it ameliorated kidney injury in cisplatin-induced AKI mice. Mitochondrial dysfunction, ATP production and respiratory capacity were improved in damaged HK-2 cells; ROS content decreased while mitochondrial membrane potential recovered. T-A-Ls exerted renal protection by inhibiting inflammation and reducing oxidative stress; these effects were mediated by a downregulation in the expression of RAGE and iNOS and an upregulation in both Nrf2 and HO-1. T-A-Ls could improve the delivery of ATS to the kidney, offering a promising avenue to treat AKI.

The relationship between sodium glucose co-transporter 2 inhibitors and diabetic ketosis/infection: single center retrospective experiences

Aims: Diabetes is a serious social problem in our country and around the world. Beyond hyperglycemia, it causes common and potentially life-threatening complications in all systems. For this reason, beyond the regulation of blood glucose, a holistic approach and combating complications are important in diabetes management. Sodium glucose co-transporter 2 inhibitors (SGLT2-i) are one of many antidiabetic drug families and stand out with their strong blood sugar regulation and cardiac and renal protective effects independent of blood sugar decrease. Despite its strong effectiveness, it is seen as risky in terms of diabetic ketosis and infection, which limits its use. We aimed to investigate the legitimacy of concerns by examining the relationship between SGLT-2 inhibitors and diabetic ketosis/infection. Methods: Our study was designed single-center and retrospectively. 152 patients over the age of 18 who were treated as inpatients in our clinic with diabetic ketosis between January 2020 and June 2023 were included in the study. In these patients, ketosis and the severity of the infection clinic, if any, were examined through various parameters among Type 2 diabetic patients using SGLT-2 inhibitors, Type 2 diabetic patients not using SGLT-2 inhibitors, and Type 1 diabetes patients. These parameters were determined by the patient's blood and urine biochemistry tests at admission and discharge, the duration of ketosis treatment, the duration of intravenous antibiotic use, and the duration of hospitalization. Results: Within the scope of the study, type 2 diabetic patients using SGLT-2 inhibitors were compared with type 2 diabetic patients not using SGLT-2 inhibitors and type 1 diabetic patients. In patients using SGLT-2 inhibitors, the leukocyte in urine, an indicator of urinary tract infection, was found to be significantly higher (p<0.002). When the blood biochemistry tests of the patients at the time of admission were compared in terms of ketosis severity, no significant difference was detected between the groups. No significant difference was detected in terms of ketosis treatment duration, intravenous antibiotic use duration, and hospitalization duration. Conclusion: We believe that we have obtained data showing that ketoacidosis and infection complications associated with SGLT-2 inhibitors are manageable and controllable. Based on this, we recommend that further research be conducted on the side effects of SGLT-2 inhibitors, emphasizing their additional systemic benefits, and that the place of these agents in diabetic treatment should be discussed.

Baicalin − 2- ethoxyethyl ester alleviates renal fibrosis by inhibiting PI3K/AKT/NF-κB signaling pathway

With the increasing incidence of chronic kidney disease (CKD), the development of safe and effective anti-renal fibrosis drugs is particularly urgent. Recently, Baicalin has been considered to have a renal protective effect, but its bioavailability is too low. Therefore, we synthesized baicalin-2-ethoxyethyl ester (BAE) by esterification of baicalin. We hope that this experiment will demonstrate the anti-renal fibrosis effect of BAE and explain its molecular mechanism. In this study, the chronic kidney injury model of SD rats was established by 5/6 nephrectomy, and BAE was given for 28 days. The results showed that after BAE treatment, the serum creatinine and urea nitrogen levels decreased significantly, and the pathological changes in kidneys were improved. In addition, RNA-seq analysis showed that the mechanism of BAE in relieving renal fibrosis was related to the ECM receptor, PI3K/AKT signaling pathway, and inflammatory reaction. The western blotting analysis confirmed that BAE could inhibit the expression of α-SMA, TGF-β1, p-PI3K, p-AKT, p-IκBα, and NF-κB p65. We found that BAE can inhibit the inflammatory reaction and promote the degradation of the extracellular matrix by inhibiting the activation of the PI3K/AKT/NF-κB pathway, thus alleviating the symptoms of renal fibrosis in 5/6Nx rats, which revealed BAE was a potential compound to relieve renal fibrosis effect.

Restoration of autophagy activity by dipsacoside B alleviates exhaustive exercise-induced kidney injury via the AMPK/mTOR pathway

Exhaustive exercise (EE) induces kidney injury, but its concrete mechanism has not been fully elucidated. Hepatoprotective effects of dipsacoside B (DB) have been found previously, involving in autophagy induction. However, whether DB exerts renal protective effect and its potential mechanism are still unknown. The present study aimed to investigate the benefit of DB in EE-induced kidney injury and decipher its underlying mechanism. Here, we found that DB ameliorated EE-induced renal dysfunction and renal histopathological injury in rats. DB possessed anti-inflammatory, anti-oxidative, and anti-apoptotic functions in kidneys of exercise-induced exhausted rats. Besides, DB improved autophagy function in kidneys of EE rats. Mechanically, activation of the adenylate-activating protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was implicated in the kidney injury-relieving effects and autophagy restoration induced by DB. Collectively, these findings provide reference for the clinical application of DB in preventing and managing EE-induced kidney injury.

Renal-protective effects of Chinese medicinal herbs and compounds for diabetic kidney disease in animal models: protocol for systematic review and meta-analysis

BackgroundDiabetic kidney disease (DKD) is a common and severe complication of diabetes that can lead to end-stage renal disease with no cure. The first-line drugs recommended by clinical guidelines fail to achieve satisfactory effects for people with DKD. A Chinese herbal medicine Tangshen Qushi Formula (TQF) shows preliminary efficacy and safety in preserving renal function for people with DKD, but the effects on comprehensive renal outcomes remain unclear. We will conduct a systematic review and meta-analysis to evaluate the effects of TQF herbs and their compounds identified from ultra-high performance liquid chromatography-MS/MS in diabetic animal models with renal outcomes.MethodsThis protocol complies with the guideline Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We will include studies investigating the effects of TQF herbs and compounds on diabetic rats or mice with renal outcomes. Six electronic databases will be searched from their inception to February 2023. Quality assessment will be conducted using SYRCLE’s risk of bias tool. Standardized or weighted mean differences will be estimated for renal outcomes (creatinine, urea, proteinuria, histological changes, oxidative stress, inflammation, and kidney fibrosis). Data will be pooled using random-effects models. Heterogeneity across studies will be expressed as I2. Sensitivity analyses will explore treatment effects in adjusted models and within subgroups. Funnel plots and Egger’s test will be used to explore publication bias.DiscussionThe results of this review will provide valuable insights into the potential effects of TQF in managing DKD. The limitation is that the included studies will be animal studies from specific databases, and the interpretation of the findings must be cautious.Systematic review registrationPROSPERO CRD42023432895. Registered on 19 July 2023 (https://www.crd.york.ac.uk/PROSPERO/#recordDetails).

Additive renal protective effects between arctigenin and puerarin in diabetic kidney disease

Recent studies have shown that the combined use of renin angiotensin system inhibitor, SGLT2 inhibitors and/or mineralocorticoid receptor antagonist provides additional renal protection for patients with diabetic kidney disease (DKD). Similarly, in traditional Chinese medicine, the synergistic application of multiple herbs often brings more significant therapeutic effects. However, the synergistic or additive mechanisms of traditional Chinese medicine in combination therapy are not fully understood. In our previous studies, we show that arctigenin (ATG), a major component of Fructus Arctii, attenuates proteinuria and renal injury in diabetic mice by activating PP2A, and puerarin (a class of known isoflavones) can also reduce proteinuria and renal injury in diabetic mice via activation of Sirt1. Here, we further explored the potential additive renal protection of these two compounds in diabetic mice. Research has found that ATG and puerarin have a synergistic effect in reducing albuminuria in db/db mice. Mechanistically, we found that ATG reduced NF-κB p65 phosphorylation likely through activation of PP2A while puerarin reduced p65 acetylation via Sirt1 activation. Therefore, ATG and puerarin have additive inhibitory effects on the NF-κB activation, which is a key inflammatory pathway in DKD. RNA-sequencing analysis revealed distinct pathways activated by ATG and puerarin in the diabetic kidney, which may provide an additional mechanism for their additive effects in DKD. Our study suggests that ATG and puerarin could be a new combination therapy for DKD and reveals its underlined mechanisms.

Sanziguben Polysaccharides Attenuate Renal Epithelial‐Mesenchymal Transition in Diabetic Nephropathy through Nrf2‐Mediated Regulation of TGF‐β1/Smad7 Signaling Pathway

Context. Sanziguben polysaccharides (SZP) have renal protection properties and can reduce renal fibrosis in diabetic nephropathy (DM). However, the mechanism of SZP’s renal protection effect is not yet clear. Objectives. Our study intended to clarify the mechanism of SZP’s renal protection effect in DM. Materials and Methods. In this study, streptozotocin‐induced C57BL/6J diabetic nephropathy mice and high glucose combined with TGF‐β1‐induced EMT in HK‐2 cells were used to investigate the effect of Sanziguben polysaccharides. ShRNA‐constructed Nrf2 knockdown HK‐2 cells were used to explore the role of Nrf2 in Sanziguben polysaccharides inhibiting epithelial‐mesenchymal transition. Results. In vivo, the results showed that Sanziguben polysaccharides improved renal epithelial‐mesenchymal transition and oxidative stress, and SZP was shown to activate the renal Nrf2, increase Smad7, and inhibit the expression of TGF‐β1 (1.05‐ to 0.71‐fold, 1.66‐ to 0.40‐fold and 0.96‐ to 1.31‐fold, respectively). In vitro, SZP ameliorated HK‐2 cell epithelial‐mesenchymal transition induced by HG combined with TGF‐β1, increased the expression of Nrf2 and Smad7, and suppressed the expression of TGF‐β1 (1.50‐ to 1.12‐fold, 1.49‐ to 1.07‐fold, and 0.94‐ to 1.38‐fold, respectively). In addition, the above effects of Sanziguben polysaccharides on Nrf2 knockdown HK‐2 cells were weakened. Conclusions. The findings suggest that Sanziguben polysaccharides may improve renal epithelial‐mesenchymal transition in diabetic nephropathy through Nrf2‐mediated regulation of TGF‐β1/Smad7 signaling pathway.

ISG15 accelerates acute kidney injury and the subsequent AKI-to-CKD transition by promoting TGFβR1 ISGylation.

Rationale: Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown. Methods: Isg15 knockout (Isg15 KO) mice challenged with bilateral or unilateral IRI, cisplatin, or UUO were used to investigate its role in AKI. We established cellular models with overexpression or knockout of ISG15 and subjected them to hypoxia-reoxygenation, cisplatin, or transforming growth factor- β1 (TGF-β1) stimulation. Renal RNA-seq data obtained from AKI models sourced from public databases and our studies, were utilized to examine the expression profiles of ISG15 and its associated genes. Additionally, published single cell RNA-seq data from human kidney allograft biopsies and mouse IRI model were analyzed to investigate the expression patterns of ISG15 and the type I TGF-β receptor (TGFβR1). Western blotting, qPCR, co-immunoprecipitation, and immunohistochemical staining assays were performed to validate our findings. Results: Alleviated pathological injury and renal function were observed in Isg15 KO mice with IRI-, cisplatin-, or UUO-induced AKI and the following AKI-to-CKD transition. In hypoxia-reoxygenation, cisplatin or TGF-β1 treated HK-2 cells, knockout ISG15 reduced stimulus-induced cell fibrosis, while overexpression of ISG15 with modification capacity exacerbated cell fibrosis. Immunoprecipitation assays demonstrated that ISG15 promoted ISGylation of TGFβR1, and inhibited its ubiquitination. Moreover, knockout of TGFβR1 blocked ISG15's fibrosis-exacerbating effect in HK-2 cells, while overexpression of TGFβR1 abolished the renal protective effect of ISG15 knockout during IRI-induced kidney injury. Conclusions: ISG15 plays an important role in the development of AKI and subsequent AKI-to-CKD transition by promoting TGFβR1 ISGylation.

Renal protective effects of Alpinate Oxyphyllae Fructus and mesenchymal stem cells co-treatment against D- galactose induced renal deterioration.

Age-related structural and functional changes in the kidney can eventually lead to development of chronic kidney disease, which is one of the leading causes of mortality among elderly people. For effective management of age-related kidney complications, it is important to identify new therapeutic interventions with minimal side-effects. The present study was designed to evaluate the synergistic effect of a traditional Chinese herb, Alpinate Oxyphyllae Fructus (AOF), and adipose-derived mesenchymal stem cells (ADMSCs) in ameliorating D-galactose (D-gal)-induced renal aging phenotypes in WKY rats. The study findings showed that D-gal-induced alteration in the kidney morphology was partly recovered by the AOF and ADMSC co-treatment. Moreover, the AOF and ADMSC co-treatment reduced the expression of proinflammatory mediators (NFkB, IL-6, and Cox2) and increased the expression of redox regulators (Nrf2 and HO-1) in the kidney, which were otherwise augmented by the D-gal treatment. Regarding kidney cell death, the AOF and ADMSC co-treatment was found to abolish the proapoptotic effects of D-gal by downregulating Bax and Bad expressions and inhibiting caspase 3 activation. Taken together, the study findings indicate that the AOF and ADMSC co-treatment protect the kidney from D-gal-induced aging by reducing cellular inflammation and oxidative stress and inhibiting renal cell death. This study can open up a new path toward developing novel therapeutic interventions using both AOF and ADMSC to effectively manage age-related renal deterioration.

Renal biochemical marker changes in renal protective effects of different doses of Aloe vera on Amphotericin B induced nephrotoxicity in Albino rats: An animal Study

Drug induced nephrotoxicity remains one of the leading causes of acute and chronic kidney diseases in Africa and other developing countries. This can be attributed to environmental pollution due to increased industrialization, poor waste disposal systems, and changes in diets among other factors. The care and treatment of these patients is extremely expensive especially when a patient requires dialysis or kidney transplant. Nephrotoxicity is normally characterized by elevated urea and creatinine levels. The aim of the present study was to evaluate these changes and draw a viable conclusion out of it. In this study a total of 25 rats were used having been calculated using modified resource equation formula. The animals were then systematically sampled and allocated to either pretreatment or treatment groups. Animals in treatment groups were subjected to similar dose of Amphotericin B and different doses of Aloe vera to achieve protection. Later animals were sacrificed humanely and blood collected through cardiac puncture and preserved for renal biochemical analysis. It was noted that there was a significant increase (P=0.0001 and P=0.0001) in both BUN and creatinine respectively in ABG group as compared to pretreatment group. There was a significant reduction (P=0.0001 and P=0.0001) in BUN and creatinine in HDAB group respectively when compared with ABG group. There was no statistical significance (P= 1.000 and P= 1.000) respectively in BUN and creatinine in HDAB group as compared to pretreatment group. It can therefore be concluded that high dose Aloe vera has renal protective benefits in Amphotericin B induced nephrotoxicity as seen in changes of biochemical parameters.

SGLT2 Inhibitors: Paradigm Shift from Diabetes Care to Metabolic Care-An Indian Perspective.

The prevalence and burden of diabetes are on the rise in India, making it 'the diabetes capital of the world'. Comorbidities such as obesity, cardiovascular (CV) complications, chronic kidney disease (CKD), non-alcoholic fatty liver disease (NAFLD), and neurodegenerative diseases are common in patients with diabetes. Recent breakthroughs in diabetes medications and continuous glucose monitoring have resulted in a paradigm shift in diabetes care. Hence, a review in the Indian context is warranted. This review focuses on the existing evidence (gathered by a systematic literature search utilising online databases such as PubMed) on the metabolic, cardio-renoprotective, and hepatoprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibition, particularly in the Indian setting. The study revealed that the SGLT2 inhibitors (SGLT2i), with their numerous pleiotropic benefits, have received considerable attention recently as a novel class of antihyperglycaemic agents (AHAs) for the management of diabetes. SGLT2i play a crucial role in the transition from glycaemic control to metabolic care, particularly in the context of obesity, CV disease and renal disease. In addition to improving glycaemic control, SGLT2i have been shown to promote weight loss, reduce blood pressure and improve lipid profiles, which are key components of metabolic health. Moreover, SGLT2i have demonstrated renal protective effects, including a reduction in albuminuria and a slower decline in the estimated glomerular filtration rate (eGFR), suggesting a potential role in the management of renal dysfunction.

Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis (ICGN). However, an in-depth study on this topic is currently lacking. Herein, we report an ICGN model to address this gap. ICGN was induced via the intravenous injection of cationized bovine serum albumin (c-BSA) into Sprague-Dawley (SD) rats for two weeks, after which mycophenolate mofetil (MMF) and losartan were administered orally. Two and six weeks after ICGN establishment, fecal samples were collected and 16S ribosomal DNA (rDNA) sequencing and untargeted metabolomic were conducted. Fecal microbiota transplantation (FMT) was conducted to determine whether gut normalization caused by MMF and losartan contributed to their renal protective effects. A gradual decline in microbial diversity and richness was accompanied by a loss of renal function. Approximately 18 genera were found to have significantly different relative abundances between the early and later stages, and Marvinbryantia and Allobaculum were markedly upregulated in both stages. Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN, characterized by the overproduction of indole and kynurenic acid, while the serotonin pathway was reduced. Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces. FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes (F/B) ratio but did not improve renal function. These findings indicate that ICGN induces serous gut dysbiosis, wherein an altered tryptophan metabolism may contribute to its progression. MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis, which partially contributed to their renoprotective effects.

Renal protective effects of natural honey on animal model of hypertension

Hypertension, also known as high blood pressure, is a leading cause of cardiovascular disease and premature death worldwide. Numerous investigations have established that hypertension can cause alterations in the cardiovascular system as well as renal structure and function. Fresh honey is consumed worldwide and is claimed to be highly medicinal and has therapeutic effects against a wide range of medical conditions. We investigated the renal protective effect of natural honey in in animal model of hypertension. Forty (40) male albino rats, with average weight (120 ±10 g) were administered with high salt diet, HSD (80 g NaCl + 1 kg of diet and 1% NaCl in drinking water (10 g of NaCl + 1 L distilled water) for 10 weeks to induce hypertension in the rats. Following confirmation, hypertensive male rats were randomly selected for the experiment. Twenty (20) albino rats (15 hypertensive rats and 5 normotensive rats) were divided into 4 groups, Groups A-D. Group A: (Normotensive Control) no administration was given; Groups B-D (hypertensive rats) received the following treatments. Group B was treated with natural honey (15 ml/kg), Group C treated with hydrochlorothiazide (0.15 mg/kg), daily for 21 days; while Group D received no treatment, until the end of the 21 days administrations. Blood samples were taken in the end, and renal alterations were assessed via biochemical and histopathological analyses. Results showed that salt-induced hypertension caused a marked elevation of the renal biochemical parameters. The histopathological results agree with the biochemical findings. However and interestingly, natural honey (15 ml/kg. oral) showed significant efficacy in the recovery and protection on the kidney as the standard anti-hypertensive drug, hydrochlorothiazide (p < 0.05 or p < 0.01). Natural honey has a renal protective effects and may manage renal hypertension or prevent kidney injury secondary to high blood pressure.

Development, optimization, and assessment of losartan nano-bilosomes to mitigate diabetes-induced microvascular complications in Sprague Dawley rats

Losartan has a significant renal protection effect in type 2 diabetic patients. It was loaded into bilosomes to overcome its low oral bioavailability and improve its renal protective effects. The bilosomes were optimized using a 23 factorial design. Bile salt type and concentration and phospholipid concentration influenced the vesicles percent drug entrapment efficiency (%EE), vesicle size (VS), polydispersity index (PDI) and zeta potential (ZP). The %EE varied from 71.73 ± 0.91 % to 92.34 ± 0.75 %. VS varied from 146.87 ± 3.56 to 286.29 ± 1.72 nm while PDI ranged from 0.28 ± 0.02 to 0.46 ± 0.03. ZP was high enough (−28.34 ± 0.61 to −35.64 ± 1.38 mV) to afford colloidal stability to the bilosomes. The bilosomes had the ability to prolong the release of the drug, with the percentage of losartan released after 12 h ranging from 64.31 ± 1.03 % to 88.48 ± 0.93 %. An optimized formulation was selected and used orally in an in vivo diabetic nephropathy rats model to study its ability to improve losartan nephroprotective effects. The diabetic group exhibited elevated serum creatinine, blood urea nitrogen (BUN), urine albumin, and inflammatory cytokines. Losartan bilosomes demonstrated reduced BUN and proteinuria compared to the free drug. Additionally, they outperformed the free drug in enhancing kidney function, preserving renal cellular structure, and mitigating diabetic renal inflammation and fibrosis. This was evidenced by significantly lower levels of tumor necrosis factor-alpha, interleukin-6, nuclear factor kappa, and macrophage markers. These findings conclusively demonstrate the promising potential of losartan bilosomes as an effective oral formulation to mitigate diabetic nephropathy.

Data mining-guided alleviation of hyperuricemia by Paeonia veitchii Lynch through inhibition of xanthine oxidase and regulation of renal urate transporters

BackgroundHyperuricemia (HUA) is a metabolic disease characterized by a high level of uric acid (UA). The extensive historical application of traditional Chinese medicine (TCM) offers a range of herbs and prescriptions used for the treatment of HUA-related disorders. However, the core herbs in the prescriptions and their mechanisms have not been sufficiently explained. PurposeOur current investigation aimed to estimate the anti-HUA effect and mechanisms of Paeonia veitchii Lynch, an herb with high use frequency identified from data mining of TCM prescriptions. MethodsPrescriptions for HUA/gout treatment were statistically analyzed through a data mining approach to determine the common nature and use frequency of their composition herbs. The chemical constituents of Paeonia veitchii extract (PVE) were analyzed by UPLC-QTOF-MS/MS, while its UA-lowering effect was further evaluated in adenosine-induced liver cells and potassium oxonate (PO) and hypoxanthine (HX)-induced HUA mice. ResultsA total of 225 prescriptions involving 246 herbs were sorted out. The properties, flavors and meridians of the appearing herbs were mainly cold, bitter and liver, respectively, while their efficacy was primarily concentrated on clearing heat and dispelling wind. Further usage frequency analysis yielded the top 20 most commonly used herbs, in which PVE presented significant inhibitory activity (IC50 = 131.33 µg/ml) against xanthine oxidase (XOD), and its constituents showed strong binding with XOD in a molecular docking study and further were experimentally validated through XOD enzymatic inhibition and surface plasmon resonance (SPR). PVE (50 to 200 μg/ml) dose-dependently decreased UA levels by inhibiting XOD expression and activity in BRL 3A liver cells. In HUA mice, oral administration of PVE exhibited a significant UA-lowering effect, which was attributed to the reduction of UA production by inhibiting XOD activity and expression, as well as the enhancement of UA excretion by regulating renal urate transporters (URAT1, GLUT9, OAT1 and ABCG2). Noticeably, all doses of PVE treatment did not cause any liver injury, and displayed a renal protective effect. ConclusionsOur results first comprehensively clarified the therapeutic effect and mechanisms of PVE against HUA through suppressing UA production and promoting UA excretion with hepatic and renal protection, suggesting that PVE could be a promising UA-lowering candidate with a desirable safety profile for the treatment of HUA and prevention of gout.

Shen Qi Wan ameliorates nephritis in chronic kidney disease via AQP1 and DEFB1 regulation

Shen Qi Wan (SQW) has been proven to exert anti-inflammatory effects in the kidneys of CKD models accompanied by unclear therapeutic mechanisms. This study aims to evaluate the kidney-protective and anti-inflammatory effects of SQW and to elucidate its fundamental mechanisms for CKD treatment. Firstly, the main active components of SQW were identified by UPLC-Q-TOF/MS technique. Subsequently, we evaluated inflammatory factors, renal function and renal pathology changes following SQW treatment utilizing adenine-induced CKD mice and aquaporin 1 knockout (AQP1-/-) mice. Additionally, we conducted RNA-seq analysis and bioinformatics analysis to predict the SQW potential therapeutic targets and anti-nephritis pathways. Simultaneously, WGCNA analysis method and machine learning algorithms were used to perform a clinical prognostic analysis of potential biomarkers in CKD patients from the GEO database and validated through clinical samples. Lipopolysaccharide-induced HK-2 cells were further used to explore the mechanism. We found that renal collagen deposition was reduced, serum inflammatory cytokine levels decreased, and renal function was improved after SQW intervention. It can be inferred that β-defensin 1 (DEFB1) may be a pivotal target, as confirmed by serum and renal tissue samples from CKD patients. Furthermore, SQW assuages inflammatory responses by fostering AQP1-mediated DEFB1 expression was confirmed in in vitro and in vivo studies. Significantly, the renal-protective effect of SQW is to some extent attenuated after AQP1 gene knockout. SQW could reduce inflammatory responses by modulating AQP1 and DEFB1. These findings underscore the potential of SQW as a promising contender for novel prevention and treatment strategies within the ambit of CKD management.

A Natural Organic Compound "Decursin" Has Both Antitumor and Renal Protective Effects: Treatment for Osteosarcoma.

Osteosarcoma is a rare malignant tumor that commonly occurs in children. Anticancer drugs, for example, cisplatin, aid in postsurgery recovery but induce side effects such as renal damage, affecting the life prognosis of patients. Decursin which is one of the bioactive components has been reported for its anti-inflammatory, antioxidant, and antitumor effects, but the effect on osteosarcoma is unexplained. In this study, the research theme was to examine the sensitizing effect of decursin and its influence on cisplatin-induced nephrotoxicity. The cell viability and half maximal inhibitory concentration (IC50), apoptosis induction, and effect on cell cycle and Akt pathways were examined. In vivo, we examine the effects of decursin on tumors and mice bodies. Additionally, the effects of the cisplatin-decursin combination were evaluated in vitro and in vivo. Decursin suppressed cell viability and induced apoptosis via the cell cycle. Decursin also inhibited the Akt pathway by suppressing the phosphorylation of Akt. It enhanced apoptosis induction and lowered cell viability in combination with cisplatin. The increasing tumor volume was suppressed in the decursin-administrated group with further suppression in combination with cisplatin compared to sole cisplatin administration. The decrease in renal function and renal epithelial cell damage caused by cisplatin was improved by the combinatorial treatment with decursin. Therefore, decursin demonstrated an antitumor effect on the osteosarcoma cells and a renal protective effect in combination with cisplatin. Therefore, decursin is a prospective therapeutic agent against osteosarcoma.

Sodium-dependent glucose transporter 2 inhibitor alleviates renal lipid deposition and improves renal oxygenation levels in newly diagnosed type 2 diabetes mellitus patients: a randomized controlled trial

BackgroundSodium-dependent glucose transporter 2 inhibitor (SGLT2i) has the advantages of effectively lowering blood glucose levels and improving renal outcomes in diabetic patients. This study evaluated the effect of canagliflozin on intrarenal lipid content and oxygenation in newly diagnosed type 2 diabetes mellitus (T2DM) patients.MethodsA total of 64 newly diagnosed T2DM patients with normal renal function were randomly divided into canagliflozin (n = 33) and glimepiride control (n = 31) groups. All patients underwent functional magnetic resonance imaging (fMRI) scanning to assay patients' intrarenal lipid content and oxygenation level before and after 24 weeks of treatment. Furthermore, the relationship between body mass index and intrarenal lipid content in T2DM patients was analyzed and the correlation between changes in intrarenal lipid content and improvements in renal hypoxia was further assessed.ResultsThe canagliflozin group had a greater decrease in body weight and blood uric acid level than the glimepiride group (all P < 0.05). The intrarenal lipid content could be significantly reduced after canagliflozin treatment for 24 weeks. The R2* values, a parameter for quantifying the oxygen content in tissues and is inversely related to the oxygen content, of the renal cortex and medulla in the canagliflozin group decreased from the baseline by 6.40% (P < 0.01) and 12.09% (P = 0.000007), respectively. In addition, the degree of reduction of fat fraction (ΔFF) in the kidneys of the canagliflozin group was correlated with the degree of improvement of oxygenation level (ΔR2*) in the renal cortex (r = 0.422, P = 0.014).ConclusionsThe early renal protective effect of SGLT2i in newly diagnosed T2DM patients may be partly attributed to the amelioration of renal hypoxia via the alleviation of ectopic lipid deposition in the kidneys.Trial Registration: Chu Hsien-I Memorial Hospital of Tianjin Medical University (ChiCTR2000037951).

GW1929 (an agonist of PPARγ) inhibits excessive production of reactive oxygen species in cisplatin-stimulated renal tubular epithelial cells, hampers cell apoptosis, and ameliorates renal injury

ABSTRACT Cisplatin-induced nephrotoxicity has long been explored for development of preventative and therapeutic drugs. The current investigation focused on the renal protective effect of GW1929, an agonist for peroxisome proliferator-activated receptors gamma (PPARγ), on cisplatin-induced kidney injury. HK2 cells treated with 20 μM cisplatin and C57BL/6 mice injected with 20 mg/kg cisplatin were used as the cell model and animal model for acute kidney injury. HK2 cell viability after cisplatin or GW1929 (0–80 μM) treatment was tested using methyl thiazolyl tetrazolium assays. Flow cytometry analysis and TUNEL assays were used to measure cell apoptosis. Intracellular reactive oxygen species (ROS) level was measured through fluorescence intensities. Levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were measured to evaluate the renal function of mice. For renal morphology observation and cell apoptosis assessment in vivo, hematoxylin-eosin staining and TUNEL assays were conducted. The concentrations of oxidative stress markers in renal samples were measured using colorimetric tests. It was found that GW1929 dose-dependently enhanced protein levels of PPARγ, PGC-1α and TFEB in HK2 cells. Meanwhile, intracellular ROS overproduction, the decrease in cell viability and excessive cell apoptosis mediated by cisplatin were reversed by GW1929. For in vivo experiments, GW1929 notably attenuated cisplatin-stimulated nephrotoxicity and oxidative stress while reducing BUN and Scr levels in cisplatin-challenged model mice. Moreover, GW1929 significantly dampened renal cell apoptosis in vivo. GW1929 mitigates renal tubular epithelial cell injury and renal damage by inhibiting oxidative stress and renal cell apoptosis.

The Effect of Sildenafil on Adenine-Induced Chronic Kidney Disease in Mice

This study was done to find the potential renal protective effects of sildenafil and its underlying mechanisms in mice with adenine-induced CKD. For the experiment, 40 male mice were split into four groups. The control group (A) received the same food without medication until the research ends, while the other three collections (B, C, and D) were given adenine (0.25% w/w in feed daily for 8 weeks), groups (C and D) were given sildenafil (0.5 and 2.5 mg/kg) respectively orally every day for 30 days, and then blood samples were taken to assess the function of the kidneys (Urea, total protein, and creatinine), total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT) in addition to kidney histopathology, as well as body and kidney weight. Administration of adenine caused weight loss, increased TAC, SOD, and CAT, and increased plasma concentrations of urea, total protein, and creatinine. Damage-related renal histopathological indicators (fibrosis and inflammation) were considerably elevated by adenine. Most of the aforementioned metrics improved with sildenafil, indicating that it might be utilized as an adjuvant treatment for CKD in people through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.