Degeneration Of Tubular Epithelial Cells Research Articles

Enhanced Kidney Damage Induced by Increasing Nonylphenol Doses: Impact on Autophagy-Related Proteins and Proinflammatory Cytokines in Rats

Nonylphenol (NP) is an organic pollutant and endocrine disruptor chemical that has harmful effects on the environment and living organisms. This study looked at whether kidney tissues subjected to increasing doses of nonylphenol generated alterations in histopathologic, pro-inflammatory, and autophagic markers. Fifty rats were divided into five groups of ten each: group I: healthy group, II: control (corn oil), group III: 25 μl/kg NP, group IV: 50 μl/kg NP, group V: 75 μl/kg NP. The kidney tissue samples were obtained for histopathological, immunohistochemical, and biochemical analyses. The histological deteriorations observed in all NP groups included tubular epithelial cell degeneration, inflammation areas, and hemorrhage. The immunohistochemical investigations showed that NP significantly elevated the autophagy markers (Beclin-1, LC3/2, p62), pro-inflammatory cytokines (TNF-α, IL-6), HIF-1α, and eNOS in group III, IV and V compared with group I and II. The biochemical analysis also revealed that pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) increased in correlation with the NP doses, but only IL-1β reached statistical significance in NP treated rats kidney tissue. The biochemical findings have been confirmed by the histological studies. The damage to renal tissue caused by NP exposure may worsen it by increasing inflammatory and autophagic markers.

A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation

BackgroundThis article reports an extremely rare case of lipoprotein glomerulopathy (LPG) with apolipoprotein E gene (APOE) Chicago mutation in a young Chinese male. Only five cases or families with APOE Chicago mutations have been reported in the literature.Case presentationThe young male patient is manifested with nephrotic syndrome, accompanied by hyperlipidemia with a preferable increase in triglycerides and elevated ApoE level. Renal biopsy of the patient showed highly dilated glomerular capillaries filled with vacuolar lipids, segmentally fused podocyte foot processes, vacuolar degeneration of renal tubular epithelial cells and absence of electron-dense material, which indicates the diagnosis of LPG. Whole-exome gene sequencing identified the heterozygous mutation of NM_000041.4:c.494G > C (p.Arg165Pro), which is in the exon 4 of the APOE gene and also known as APOE Chicago mutation, a rare mutation of LPG. Further family pedigree gene analysis clarified that the mutation was inherited from the patient’s mother, who does not have high ApoE levels or renal manifestations. This is also consistent with the incomplete penetrance of APOE gene mutations in LPG. Under lipid-lowering treatments, including a low-fat diet and fenofibrate, the patient’s urinary protein was partially controlled, and the albumin level was recovered.ConclusionPatients with nephrotic syndrome and elevated ApoE levels should be prompted into renal biopsy to avoid delay of appropriate treatment and unnecessary use of glucocorticoids. This case of LPG was diagnosed by renal biopsy and further verified with genetic sequencing. The timely diagnosis and treatment improved the patient’s symptoms. This case is one of only six reported LPG cases or families with APOE Chicago mutation in the world.

Preliminary study of the role of nanobacteria in the formation of renal stones in experimental rats and its mechanism.

The aim of the study was to study the role of nanobacteria in the formation of renal calculi and the underlying mechanism. A total of 90 clean Wistar male rats were randomly divided into a negative control group, an experimental group, and an interference group. From the end of the first week of modelling, 10 consecutive times once a week, 3 rats in each group were randomly selected to measure the biochemical blood markers and urine metabolism. After sacrifice, the formation of kidney stones was assessed by observing the ultrastructure of the kidney by electron microscopy and pathohistology. Finally, the expression of calcium-sensitive receptor (CaSR) and claudin-14 protein in the kidney tissue was examined by western blotting. Compared with the control group, the gross structure of the kidney was changed in the model group. At the fourth week of modelling, the rats in the nanobacteria group had significantly enlarged kidneys and increased kidney-to-body ratio, and the difference had statistical significance (p < 0.05). The colour of the kidney profile was dark, the structure of the skin pulp was less clear, and the accumulation of yellowish particles was observed at the junction of the cortical pulp. The creatinine, uric acid, urea nitrogen, and urinary calcium of the rats in the nanobacteria group began to increase at the third week, and the difference between the third and eighth week had statistical significance (p < 0.05). However, the difference between the 3 groups had no statistical significance after the eighth week. At the fourth week, we observed the formation of calculi, which were mainly distributed in the renal tubules and surrounding tissues. The kidney stone formation rate was 52.4% in the nanobacteria group and 27.8% in the interference group, and the difference had statistical significance (p < 0.05). Ultrastructure observations revealed that from the fourth week, the renal tissues in the nanobacteria group showed expanded renal tubules, swollen renal tubular epithelium, granular degeneration, shedding and lymphocyte infiltration of renal tubular epithelial cells, and a small amount of calcium salt crystals in renal tubules. At the third week, the expression of CaSR and Claudin-14 protein in the nanobacteria group increased, and the difference had statistical significance (p < 0.05). The expression of CaSR and Claudin-14 was positively correlated with urinary calcium (p < 0.05). The formation of renal calculi began in the fourth week after the model was established, and the crystals were mostly located in the renal tubules. During the formation of renal calculi, the renal tubular epithelial cells were damaged, showing granular degeneration and small amounts of calcium salt crystals, accompanied by a few renal tubules beginning to expand and epithelial swelling, granular degeneration, necrosis and shedding of renal tubular epithelial cells, lymphocyte infiltration in the renal interstitium, and small amounts of calcium salt crystals in the renal tubules, which aggravated with time. The serum creatinine, serum uric acid, urea nitrogen, and urinary calcium levels increased with time from the third week and returned to normal after the eighth week. The expression of CaSR and Claudin-14 protein was upregulated and positively correlated with the 24-h urinary calcium excretion value.

A perspective of the prevalent H9N2 virus with a special focus on molecular and pathological aspects in commercial broiler chicken in Punjab, Pakistan.

Frequent outbreaks of avian influenza H9N2 virus in Pakistan revealed that this subtype has become endemic in the poultry industry and, besides economic losses, poses a threat to public health. The present study describes the molecular characterization and pathological alterations in naturally infected broiler chickens with the current H9N2 field strain and their phylogenomic dynamics. In this study, tissue samples (trachea, lung, kidney and intestine) from 100 commercial chicken flocks were collected from July 2018 to August 2019. Samples were subjected to molecular detection, phylogeny and subsequent pathological examination. The complete length of the HA gene was successfully amplified in five samples. Nucleotide sequencing revealed positive samples placed in a clade belonging to the B2 sub-lineage of the G1 genotype and categorized as LPAIV based on the amino acid sequence of the HA gene at the cleavage site (PAKSSR/G). Genetic analysis of the haemagglutinin (HA) gene revealed nt: 80.5%-99.5%; aa: 83.8%-98.9% homology to H9N2 strains reported previously from Pakistan, neighbouring countries, and (A/Quail/Hong Kong/G1/97). Gross lesions include a slight airsacculitis, mild hemorrhages, diffuse congestion and purulent exudate in tracheal mucosa, fibrinonecrotic cast in the trachea lumen and mild pulmonary congestion. Histopathological alterations include sloughing of epithelial cells and infiltration of inflammatory cells in the trachea, mononuclear cells (MNCs) infiltration, pulmonary congestion and exudate in the lumen of parabronchi, peritubular congestion in the kidneys with degeneration of tubular epithelial cells and degenerative changes in the intestinal villi epithelial cells and goblet cell hyperplasia. Immunohistochemistry analysis confirmed the presence of AIVH9N2 antigen in the trachea, lungs, kidney and intestine. Electron microscopy revealed ultrastructural changes in the trachea, including degenerated cilia, mitochondrial swelling and enlarged endoplasmic reticulum. Based on all essential analysis, the present study revealed the distribution of the H9N2 virus of G1 genotype in Punjab, Pakistan, with mild to moderate pathogenicity.

Intoxicações por anti-helmínticos em pequenos ruminantes diagnosticadas no Nordeste do Brasil

ABSTRACT: The clinical, epidemiological and anatomopathological findings of anthelmintic poisoning in small ruminants diagnosed at the Veterinary Hospital of the Federal University of Campina Grande, Patos, Paraíba, from January 2000 to December 2022 are described. A total of 1,928 necropsies were carried out on small ruminants, of which 1,032 were goats and 896 sheep. Four outbreaks of anthelmintic poisoning were identified in these species: one outbreak of ivermectin in sheep, one outbreak of disophenol in goats and sheep and two outbreaks of nitroxinil in goats. These intoxications accounted for 0.78% and 0.23% of goat and sheep diseases diagnosed routinely. In the case of ivermectin poisoning, the animal had neurological clinical signs, and no macroscopic or histopathological alterations were observed. In the outbreaks of disophenol and nitroxinil, the animals showed anorexia, hyperthermia, tachycardia, tremors, dyspnea, incoordination and limb rigidity. Macroscopically, there were liver and kidney lesions associated with circulatory alterations, such as hemorrhages and edema. Microscopically, necrosis and degeneration of hepatocytes and tubular epithelial cells associated with hemorrhage and congestion were observed. The prevalence of these intoxications in small ruminants is considered low in the Semi-arid Northeast, but outbreaks can occur with high lethality in herds. The main risk factor for the occurrence of intoxications was overdose, combined with other factors such as the age of the animals, high environmental temperature, constant exercise and low body score, which increased the toxicity of anthelmintics.

Moth Bean (Vigna aconitifolia) as Potential Supplement to Evaluate the Weight Gain in Wistar Albino Rats (Rattus norvegicus)

Vigna aconitifolia is an essential crop in Indian agriculture, predominantly cultivated in India. It is acknowledged for its significant nutritional value and its affordability, making it a valuable dietary choice for individuals facing economic challenges. This study investigates the potential of ungerminated and germinated Vigna aconitifolia seeds as a dietary supplement to evaluate their effects on weight growth and general health in Wistar Albino Rats. The Wistar Albino Rats were categorized into three groups viz., Group I (Control), Group II (Fed with ungerminated Vigna aconitifolia) and Group III (Fed with germinated Vigna aconitifolia). The rats were given unrestricted access to water and food for a duration of 28 days. Water and food consumption and changes in body weight were observed on days 1, 7, 14, 21 and 28. On day 29, animals were killed and their kidneys and intestines histopathologically examined. Although the ungerminated and germinated groups consumed similar amounts of water, both consumed more than the control group. On the 28th day, ungerminated Vigna aconitifolia had significantly lower food intake compared to germinated and regular feed groups (P&lt;0.05). Rats given both ungerminated and germinated seeds gained more weight. All groups had normal kidney histology, with no tubular epithelial cell degeneration or congestion. Rats administered ungerminated and germinated Vigna aconitifolia had villi, mucus-secreting epithelium and glands in their ileums but no hyperplasia or edema. The study found that Wistar Albino Rats gain weight when supplemented with germinated Vigna aconitifolia. This shows it could be a growth-promoting nutritional supplement. Further research is needed to determine the fundamental processes behind the claimed effects.

Effects of Graded Doses of Ethanolic Extract of Pausinystalia Yohimbe Stem Bark on Biochemical and Hematological Indices In the Kidneys of Female Wistar Rats

Pausinystalia yohimbe is a medicinal plant widely used as an aphrodisiac agent in Nigeria and other parts of West Africa, but little is known about its effect on renal function after chronic use. This study was designed to investigate the effect of ethanolic extract of Pausinystalia yohimbe stem bark on renal function parameters such as serum creatinine, urea, electrolyte, oxidative stress markers, and hematological parameters in female Wistar rats. Ethanolic extract of Pausinystalia yohimbe stem bark was administered orally to 3 groups of 5 female rats for 21 days as follows: group1 which served as control received distilled water while groups 2 and 3 received 400mg/kg and 800mg/kg body weight of the extract respectively. Thereafter the rats were sacrificed, and blood and kidney tissues were collected for biochemical analysis. The result showed that there were no significant changes in urea, creatinine, potassium, chloride, and bicarbonate levels while sodium level was significantly increased (p&lt;0.05) when compared to the control. SOD and CAT tissue activities did not show any significant change (p&lt;0.05) while there was a significant increase (p&lt;0.05) in GSH and a significant reduction (p&lt;0.05) in MDA. Also, there was no significant change (p&lt;0.05) in WBC, PCV, and platelets, however, there was a significant decrease (p&lt;0.05) in RBC and hemoglobin levels. The histopathology of the kidney showed that no significant changes were observed between treatment groups and control except for the 800 mg/kg body weight of the extract-treated group where there was mild multifocal vacuolar degeneration of some renal tubular epithelial cells. The result suggests that the chronic use of the ethanolic extract of Pausinystalia yohimbe stem bark protects the kidney against oxidative stress but adversely affects the functional capacities of the kidney and formation of erythropoietin in the stem cells and may also contribute to the increasing number of persons with high blood pressure.

Effects of exogenous advanced glycation end products on oxidative stress and renal injury in healthy mice

AbstractThis study evaluated the biological effects of exogenous advanced glycation end products (AGEs) on the induction of chronic kidney disease and the dose‐effect relationship. Male C57BL/6 mice were placed on four diets, including saline and three other diets differing only in AGEs content (low‐AGEs [LA], medium‐AGEs [MA], and high‐AGEs [HA] ratio, 1:3:5) for 4 weeks. With the increasing intake of AGEs, mice developed a significant increase in blood glucose and lipid levels, the fluorescence intensity of AGEs, Nε‐(carboxymethyl)‐lysine, Nε‐(carboxyethyl)‐lysine, and malondialdehyde levels, whereas their superoxide dismutase activity and glutathione levels were decreased significantly. HA had the highest urinary protein levels and the lowest creatinine clearance compared to the other groups. These suggested that AGEs are an essential contributor to increasing oxidative stress levels and intake of high‐level AGEs induces more severe kidney function impairment. Meanwhile, the AGEs intake damaged the kidney structure in a dose‐dependent manner, as evidenced by granular degeneration of kidney tubular epithelial cells and inflammatory cell infiltration. These findings shed light on the detrimental impacts of AGEs on human kidneys, which also will help reveal a dose‐effect relationship of AGEs.

Development of liposomal contrast agent with high iodine concentration and minimal effect on renal function

PurposeThe use of contrast media is essential to achieve high accuracy in diagnostic imaging. Iodine contrast media, one of these contrast media, has nephrotoxicity as a side effect. Therefore, the development of iodine contrast media that can reduce nephrotoxicity is expected. Since liposomes are generally adjustable in size (100–300 nm) and are not filtered by the renal glomerulus, we hypothesized that iodine contrast media could be encapsulated in liposomes and administered to avoid the nephrotoxicity of iodine contrast media. The aim of this study is to develop an iomeprol-containing liposome (IPL) agent with high iodine concentration and to investigate the effect of intravenous administration of IPL on renal function in a rat model with chronic kidney injury. Materials and methodsIPLs were prepared by encapsulating an iomeprol (400mgI/mL) solution in liposomes by a kneading method using a rotation–revolution mixer. Radiodensities of iomeprol and IPL were measured. IPL or iopamidol at normal dose (0.74 g I/kg) or high dose (3.7 g I/kg) was administered to healthy and 5/6-nephrectomized rats (n = 3–6). Serum creatinine (sCr) and histopathological change of tubular epithelial cells were evaluated after injection. ResultsThe iodine concentration of IPL was 220.7 mgI/mL, equivalent to 55.2% of the iodine concentration of iomeprol. The CT values of IPL was 4731.6 ± 53.2 HU, 59.04% that of iomeprol. The ratios of change in sCr in 5/6-nephrectomized rats that received high-dose iopamidol were 0.73, which were significantly higher than that in 5/6-nephrectomized rats that received high-dose IPL (−0.03) (p = 0.006). Change in foamy degeneration of tubular epithelial cells was confirmed in 5/6-nephrectomized rats that received high-dose iopamidol than that in the sham control group and healthy rats that received normal dose iopamiron (p = 0.016, p = 0.032, respectively). Foamy degeneration of tubular epitherial cells was rarely observed in the IPL injection group. ConclusionsWe developed new liposomal contrast agents that have high iodine concentration and minimal effect on renal function.

Sıçanlarda Doksorubisin Kaynaklı Böbrek Hasarı Üzerine Selenyum ve N-(p-Amilsinnamoil) Antranilik Asit’in Etkisi

Doxorubicin (DOXR) is one of the essential antitumor drugs. However, its serious adverse effects in many organs limit the clinical use of DOXR. This study aimed to investigate the effect of selenium (Se) and N-(p-Amilcinnamoyl) anthranilic acid (ACA) on kidney tissue in DOXR-administered rats. The rats in the study were divided into six groups (n=10); Control, DMSO, DOXR, DOXR+Se, DOXR+ACA and DOXR+Se+ACA. At the end of the study, intracardiac blood was drawn from rats, and kidney tissues were removed. Urea and creatine levels were measured in serum samples of rats. In addition, histopathological examination of kidney tissue was determined by H&amp;amp;E staining, and 8-OHdG expression was determined by immunohistochemical analysis. Urea and creatine levels increased with DOXR decreased in serum samples after Se and ACA treatments (p&amp;lt; 0.05). While glomerular atrophy, tubular and glomerular dilatation, vascular occlusion and degeneration of tubular epithelial cells were observed in the DOXR group, significant improvement was observed in the Se and ACA treatment groups. In addition, Se and ACA treatments reduced DOXR-induced 8-OHdG expression (p&amp;lt; 0.05). These findings indicated that Se and ACA could be used as critical therapeutic agents to suppress renal dysfunction and oxidative DNA damage that can occur after DOXR-induced kidney injury.

The impact of heat stress on oxidative stress and histopathological dynamics in red hybrid tilapia experimentally infected with Streptococcus agalactiae

The most common predisposing factor to Streptococcosis in the aquaculture industry is heat stress. The impact of heat stress on oxidative stress and histopathological changes in red tilapia with Streptococcosis is not well understood. This study aimed at evaluating the impact of heat stress on oxidative stress and histopathological dynamics in red hybrid tilapia experimentally infected with Streptococcus agalactiae. Apparently healthy 105 red hybrid tilapia (Oreochromis nolyticus) were used. The fish weighing 120 to 130 g were acclimatized for 2 days prior to onset of the experiment. The 105 tilapias were randomly separated to group 1, group 2 and group 3 of 35 fishes each in 200 litre tanks. Group 1 was inoculated with 0.1 mL of S. agalactiae at 109 CFU/mL intraperitoneally and subjected to heat stress (33°C). Group 2 was injected intraperitoneally with the same quantity of S. agalactiae in similar manner to group 1 without heat stress as positive control while group 3 served as negative control. Samples of blood was collected from five fish in every group before and at 6, 12, 24, 48, 72 h and 96 hours post-inoculation (pi) for lipid peroxidation [malondialdehyde (MDA)] and erythrocyte superoxide dismutase (SOD) analysis. The fish were necropsied and samples were taken from spleen, liver and kidney for microbiology and histopathology. Statistical analysis from the value of MDA and SOD revealed that there were significant differences (p &lt; 0.05) between all the groups. Predominant lesions in the spleen were hemosiderin deposition, lymphoid depletion and haemorrhages. In the liver, main lesions were hepatocellular necrosis, mononuclear cell infiltration and haemorrhages while in the kidney, predominant histopathological lesions were mononuclear cell infiltration, necrosis, degeneration of tubular epithelial cells and haemorrhages. The lesions were significantly higher in spleen, liver and kidney of fish in group 1, followed by group 2 as compared to 3 which had no significant histological damage. Based on the findings of this study, heat stress alters significantly, the oxidative stress status and histopathology of Streptococcus infection in red hybrid tilapia.

Protective effects of peanut skin extract on high-fat and high-fructose diet-induced kidney injury in rats.

Chronic kidney disease (CKD) is becoming a major public health problem worldwide. This study aimed to explore whether peanut skin extract (PSE) has protective effects against high-fat and high-fructose (HF) diet-induced kidney injury. Rats were fed HF diet in the whole experiment, while rats in PSE-treated groups were supplemented with PSE. Finally, PSE reduced kidney tissue weight, perinephric fat weight, and levels of serum ammonia, creatinine, and urea nitrogen, along with decreases of renal IL-1β and TNF-α level. Histological examination indicated that PSE alleviated renal tubular dilatation, and degeneration and partial exfoliation of renal tubular epithelial cells. In addition, PSE decreased serum and urinary uric acid level, together with reductions of XOD production and XOD activity both in serum and liver, and down-regulated expressions of renal NLRP3 and ERS proteins. Thus, PSE may be a potential functional food for protecting against renal injury in high energy intake.

Rosiglitazone attenuates hypoxia-induced renal cell apoptosis by inhibiting NF-κB signaling pathway in a PPARγ-dependent manner

Background In recent years, peroxisome proliferator-activated receptor γ (PPARγ) has been found to be closely associated with hypoxia renal disease. The aim of this study was to investigate the relationship between rosiglitazone and mitochondrial apoptosis in renal tissue and its associated mechanisms. Methods Twenty-four male Sprague-Dawley rats were randomly divided into three groups (n = 8 in each): normal control group, hypoxia injury group (equal volume of 0.9% saline), and PPARγ agonist group (Rosiglitazone, 10 mg/kg · d, intraperitoneally). The hypoxia injury group and PPARγ agonist group were placed in a hypoxia chamber and the simulated altitude was set at 7,000 m for 7 days. Blood and kidney samples were collected after 7 days. The quantitative real-time polymerase chain reaction and Western blot methods were used to determine the expression of PPARγ, nuclear factor kappa-B (NF-κB), B-cell lymphoma-2 (Bcl-2), and Bax. Results The results showed that compared with the normal control group, the renal tissue of rats after hypoxia was severely damaged, as shown by massive renal tubular epithelial cell degeneration and detachment, and renal tubular dilation. The NF-κB protein expression significantly increased, the Bcl-2 protein and mRNA expression significantly decreased, and Bax protein and mRNA expression significantly increased (p < .05 for all). Renal injury was much less severe in the PPARγ agonist group compared to the hypoxia injury group. Conclusions Rosiglitazone can alleviate hypoxia renal injury, with the possible mechanism involving attenuation of apoptosis by inhibiting the activation of the NF-κB signaling pathway in a PPARγ-dependent manner and increasing Bcl-2 and decreasing Bax expression.

Yishen Capsule Alleviated Symptoms of Diabetic Nephropathy via NOD-like Receptor Signaling Pathway

PurposeTo explore the mechanism of Yishen capsule against diabetic nephropathy (DN) based on the analysis of transcriptomics.Material and MethodsSD rats (Male, SPF grade) were randomly divided into four groups, the normal group, the DN group, the Yishen capsule group and the resveratrol group. Urine and renal tissue samples were collected after feeding with physiological saline and above drugs for 8 weeks. 24-hour urine microalbumin protein was detected by ELISA. HE staining and PAS staining were performed on renal tissues. Differential gene expression in renal tissues was analyzed by transcriptome sequencing. The differentially expressed genes were analyzed by GO enrichment and KEGG enrichment, and verified by RT-PCR and immunohistochemistry staining.ResultsThe level of 24-hour urinary microalbumin in DN group was increased, while Yishen capsule treatment reversed the increasement of urinary microalbumin. Mesangial cell proliferation, matrix accumulation, edema and vacuolar degeneration of renal tubular epithelial cells and glycogen accumulation were observed in DN group. However, pathological phenotypes mentioned above were alleviated after Yisen capsule administration. This result indicates that Yishen capsule reversed pathological phenotypes of DN in rats. The expression of 261 genes were changed in Yishen capsule group compared with DN group. GO enrichment analysis and KEGG pathway analysis showed that these genes were implicated in pathways, including mineral absorption, adipocytokine signaling pathway, fatty acid biosynthesis, thyroid hormone synthesis, renin–angiotensin system, and NOD-like receptor signaling pathway. Based on previous reported study, the expression of key factors in NOD-like receptor signaling pathway was verified. RT-PCR and immunohistochemistry staining showed that the expression of NLRP3, Caspase-1 and IL-1β in renal tissues of DN group were increased (P < 0.05), which were decreased in Yishen capsule group (P < 0.05).ConclusionYishen capsule reduced microalbuminuria and alleviated pathological changes in DN rats, which may be achieved by regulating NOD-like receptor signaling pathway.

Oral subacute nephrotoxicity of aristololactam I in rats

Aristolactams (ALs) have been recognized as one kind of metabolites of aristolochic acids (AAs), the nephrotoxic components of Aristolochiaceae plants, and are more widely distributed than AAs in herbal medicines. This study evaluated the oral subacute nephrotoxicity of aristolactam I (AL I), a representative compound of ALs. AL I was intragastrically administered to rats at 20 mg·kg−1·d−1 for 10 or 20 days, with aristolochic acid I (AA I) used as positive control at the same dose. After 10-day treatment, AL I led to a significant increase in early renal injury-related indices in urine and obvious histopathological lesions in kidneys, including degeneration of tubular epithelial cells, inflammatory cell infiltration and fibrosis. The lesions induced by AL I were significantly aggravated after 20-day exposure. However, AL I induced less histopathological damage in kidneys than AA I in both 10- and 20-day groups. Our results indicated that oral AL I caused nephrotoxicity by inducing oxidative stress, inflammation, and overactivation of the complement system as AA I did. Three detected apoptosis-associated indicators were not affected by AL I but remarkably increased by AA I. In summary, oral AL I induced evident renal damage in rats after only 10 days of treatment, and the damage was aggravated after 20 days. However, AL I was obviously less nephrotoxic than AA I via oral gavage.

Knockout of farnesoid X receptor gene aggravates cisplatin-induced kidney injury.

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors and belongs to bile acid receptor. Studies have shown that the expression of FXR in renal tissue can reduce renal injury via regulation of glucose and lipid metabolism, inhibition of inflammatory response, reduction of oxidative stress and renal fibrosis. However, it is unclear whether FXR is involved in autophagy in renal diseases. This study aims to investigate the role of FXR in cisplatin-induced acute renal injury and whether its mechanism is related to autophagy regulation. Twelve male WT or FXR-KO mice at 12 weeks were randomly divided into a WT group, a WT+cisplatin group, a FXR-KO group, and a FXR-KO+cisplatin group, with 6 mice in each group. The WT+cisplatin group and the FXR-KO+cisplatin group were intraperitoneally injected with cisplatin (20 mg/kg), and the WT group and the FXR-KO group were intraperitoneally injected with equal volume of cisplatin solvent. Seventy-two hours later, the mice were killed and blood and renal tissue samples were collected. The levels of SCr and BUN were detected by immunoturbidimetry. After the staining, the pathological changes of renal tissue were observed under optical microscope. The protein levels of LC3 and p62 were detected by Western blotting and immunohistochemistry. The clearance of damaged mitochondria and the accumulation of lysosomal substrate were observed under electron microscope. The apoptosis of renal tubular epithelial cells was detected by TUNEL. Compared with the WT group or the FXR-KO group, both SCr and BUN levels in the WT+cisplatin group or the FXR-KO+cisplatin group were significantly increased (P<0.01 or P<0.001), and SCr and BUN levels in the FXR-KO+cisplatin group were significantly higher than those in the WT+cisplatin group (both P<0.05). Under the light microscope, there were no obvious pathological changes in the renal tissue of mice in the WT group and the FXR-KO group. Both the WT+cisplatin group and the FXR-KO+cisplatin group had vacuolar or granular degeneration of renal tubular epithelial cells, flat cells, lumen expansion, brush edge falling off, and even exposed basement membrane and tubular formation. The scores of renal tubular injury in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the score in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Under the transmission electron microscope, the mitochondria of mouse tubular epithelial cell in the WT+cisplatin group and the FXR-KO+cisplatin group was swollen, round, vacuolated, cristae broken or disappeared; the lysosome was uneven and high-density clumps, and the change was more obvious in the FXR-KO+cisplatin group. Western blotting showed that the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased in the WT+cisplatin group compared with the WT group and the FXR-KO+cisplatin group compared with FXR-KO group (P<0.05 or P<0.01); compared with the FXR-KO group, the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased significantly in the FXR-KO+cisplatin group (both P<0.05). Immunohistochemistry results showed that the expression of total LC3 and p62 in renal cortex of the WT+cisplatin group and the FXR-KO+cisplatin group was increased significantly, especially in the FXR-KO+cisplatin group. TUNEL results showed that the mice in the WT group and the FXR-KO group had negative staining or only a few apoptotic tubular epithelial cells, and the number of apoptotic cells in the WT+cisplatin group and the FXR-KO+cisplatin group were increased. The apoptosis rates of renal tubular epithelial cells in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the apoptosis rate in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.

Dexmedetomidine inhibits oxidative stress in sepsis-induced acute kidney injury in rats by regulating GSK-3β/Nrf2/ARE axis

Purpose: To determine the effect of dexmedetomidine on sepsis-mediated acute kidney injury (SAKI) in rats.&#x0D; Methods: Twenty-four SD rats were randomly divided into blank untreated control group, model group given lipopolysaccharide at a dose of 10 mg/kg, dexmedetomidine (Dex) group, and glycogen synthase kinase-3 beta (GSK-3β) inhibitor group given sb216763. In addition, Dex and inhibitor groups received the same dose of lipopolysaccharide as model group. There were 10 rats in each group. Pathological changes in kidney tissue, and the levels of related oxidative stress indices were determined.&#x0D; Results: Compared with the model group, granular degeneration of renal tubular epithelial cells was significantly reduced in Dex group, and the population of exfoliated cells decreased (p &lt; 0.05). The levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in dexmedetomidine and GSK-3β inhibitor groups were significantly reduced, while superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) activities were markedly raised, relative to model group (p &lt; 0.05). Protein levels of p- GSK-3β and Nrf2 markedly were raised in dexmedetomidine and GSK-3β inhibitor groups (p &lt; 0.01). After intervention with Dex and GSK-3β inhibitor, there were marked upregulations in mRNA and protein expression levels of heme oxygenase-1 (HO-1), when compared with model group (p &lt; 0.05).&#x0D; Conclusion: Dexmedetomidine ameliorates SAKI injury in rats via suppression of oxidative stress. Its mechanism of action may be related to the regulation of GSK-3β/Nrf2/ARE signaling pathway. This finding may be a novel approach to the clinical management of SAKI.

Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney.

Molybdenum (Mo), fundamental trace mineral for animals and plants, but undue Mo damages animal health. Cadmium (Cd) is a toxic heavy metal that exists in the environment. Nevertheless, the mechanism of Mo and Cd on mitochondrial quality control are still indistinct. The objective of this research was to explore the effects of mitophagy on mitochondrial quality control via the FUNDC1-mediated by Mo and Cd in sheep kidney. Forty-eight 2-month-old sheep were stochastically divided into four groups, as shown below: control group, Mo [45 mg/kg body weight (BW)] group, Cd (1 mg/kg BW) group and Mo (45 mg/kg BW)+Cd (1 mg/kg BW) group, with 50 days feed technique. The results showed that Mo or/and Cd attract an unbalance of trace minerals and vacuoles and granular degeneration of renal tubular epithelial cells, and increase the number of mitophagosomes and vacuole-mitochondria and LC3 puncta and MDA and H2O2 contents, and decrease ATP content in the kidney. Moreover, Mo or/and Cd treatment could upregulate the mRNA levels of FUNDC1, LC3A, LC3B, PGAM5, DRP1, FIS1 and MFF, and the protein levels of FUNDC1, p-FUNDC1, LC3II/LC3I, DRP1, MFF and FIS1, downregulate the mRNA levels of MFN1, MFN2, OPA1, PGC-1α, SIRT1, SIRT3, FOXO1 and FOXO3, and the protein levels of MFN1, MFN2, OPA1 and PGC-1α. Notably, variations of above-mentioned factors in Mo and Cd group were more obvious than in Mo or Cd groups. Taken together, these results displayed that Mo and Cd co-treatment might induce mitochondrial quality control disorder via FUNDC1-mediated mitophagy in sheep kidney.

Assessment of cyto-nephrotoxicity and growth performance in Labeo rohita induced by fluorescein dye Y and B

The cyto-nephrotoxicity in fishes induced by dyes is a global issue. Fluorescein dye has a wide range of applications in industry and biological laboratories. In vivo experiment was planned to assess the sublethal effects of Fluorescein dye, Eosin Y, and Eosin B in Labeo rohita. This freshwater fish was exposed to increasing concentrations (0.0011, 0.0023, and 0.0047 mg/L) of both dyes in the aquarium for definite time intervals. A dye-free trial was set as a control. Fish was anesthetized and dissected by cutting on the ventral side to remove a kidney. Cyto-nephrotoxicity was detected through histopathology. The fish's significant mortality was observed when exposed to 0.0023 mg/L (LC50) and 0.0047 mg/L concentration of Eosin Y dye. These trial groups showed many kidney tissues alterations such as glomerular, tubular epithelial cell's degeneration, a reduced lumen of tubules, vacuolation, absence of bowmen's space, necrosis, glomerulonephritis with increased per tubular space, shrinking of the glomerulus, congestion, clogging, and degeneration of tubules. Eosin B showed less mortality and tissue damage, including glomerular contraction and increased space between glomerulus and capsule. ANOVA showed a highly significant reduction in weight gain of fish at different treatments levels of Eosin Y, but less or none in the case of Eosin B. Increase in fish weight was found to be 66.3 ± 0.38 g when exposed to Eosin Y at 0.0047 mg/L, but it was 69.05 ± 0.63 g when exposed to Eosin B while it was almost identical 69.2 ± 0.23 g for both dye-free trial groups. The pair-wise comparison showed that exposure of the Eosin Y at treatment level 0.0047 mg/L was found to be highly toxic for the kidneys of Labeo rohita. Although both classes of dye are cytotoxic at small concentrations, Eosin Y is acute cyto-nephrotoxic and was found to be involved in growth retardation. To prevent society from fatal consequences, usage of dyes having acute toxicity must be banned or switched to alternates having no effects.

​Safety Evaluation of Andrographolide-nanosuspensions

Background: Andrographolide (ANDRO) is a hydrophobic drug, which faces the problem of limited absorption due to poor water solubility. The current research prepared andrographolide nanosuspensions (ANDRO-NS) and examined in vivo toxicity for mice. Methods: ANDRO-NS were prepared by anti-solvent precipitation method, transmission electron micrographs, granularity analysis and in vitro release were used to characterize the ANDRO-NS, we evaluate the safety of the ANDRO-NS by using the acute toxicity test, local irritation test and chronic toxicity test. Result: The particle size of ANDRO-NS was (568.51±13.74 nm). The LD50 for ANDRO-NS was 548.91 mg/kg after oral administration to KM mice with a 95% CI of 468.19-645.03 mg/kg. The white blood cell counts and hemoglobin levels for the experimental groups were lower than controls receiving only saline. Serum aspartate transaminase, creatinine and blood urea nitrogen levels were greater than controls after 7 and 14 days of once-daily administration. After 14 days of administration, the platelet counts as well asalanine transaminase levels were, in addition, Histological observations indicated that interstitial kidney tissues were wider than controls and showed episodic bleeding after 7 days of administration. The highest dose administered also resulted in the dilation and blood engorgement of the central hepatic veins with some severed hepatic cords. Mice receiving the lowest dose of ANDRO-NS we administered appeared healthy and similar to controls receiving saline only. Following 14 days of administration, we found significant vacuolar degeneration of renal tubular epithelial cells and glomerular atrophy for the high-dose group as well as edema and necrosis in liver cells. The medium-dose group displayed kidney interstitial tissue widening with scattered bleeding, inflammatory cell infiltration and hepatocyte edema. The low-dose group displayed dilated renal tubules and irregularly-arranged liver cells as well as bleeding in the hepatic sinusoids. Therefore, short-term administration of andrographolide suspensions resulted in inflammation and time- and dose-dependent toxic effects on the kidneys and liver.