Renal Histopathological Alterations Research Articles

Novel thiazolidin-4-one benzenesulfonamide hybrids as PPARγ agonists: Design, synthesis and in vivo anti-diabetic evaluation

In the current study, two series of novel thiazolidin-4-one benzenesulfonamide arylidene hybrids 9a-l and 10a-f were designed, synthesized and tested in vitro for their PPARɣ agonistic activity. The phenethyl thiazolidin-4-one sulphonamide 9l showed the highest PPARɣ activation % by 41.7%. Whereas, the 3-methoxy- and 4-methyl-4-benzyloxy thiazolidin-4-one sulphonamides 9i, and 9k revealed moderate PPARɣ activation % of 31.7, and 32.8%, respectively, in addition, the 3-methoxy-3-benzyloxy thiazolidin-4-one sulphonamide 10d showed PPARɣ activation % of 33.7% compared to pioglitazone. Compounds 9b, 9i, 9k, 9l, and 10d revealed higher selectivity to PPARɣ over the PPARδ, and PPARα isoforms. An immunohistochemical study was performed in HepG-2 cells to confirm the PPARɣ protein expression for the most active compounds. Compounds 9i, 9k, and 10d showed higher PPARɣ expression than that of pioglitazone. Pharmacological studies were also performed to determine the anti-diabetic activity in rats at a dose of 36 mg/kg, and it was revealed that compounds 9i and 10d improved insulin secretion as well as anti-diabetic effects. The 3-methoxy-4-benzyloxy thiazolidin-4-one sulphonamide 9i showed a better anti-diabetic activity than pioglitazone. Moreover, it showed a rise in blood insulin by 4-folds and C-peptide levels by 48.8%, as well as improved insulin sensitivity. Moreover, compound 9i improved diabetic complications as evidenced by decreasing liver serum enzymes, restoration of total protein and kidney functions. Besides, it combated oxidative stress status and exerted anti-hyperlipidemic effect. Compound 9i showed a superior activity by normalizing some parameters and amelioration of pancreatic, hepatic, and renal histopathological alterations caused by STZ-induction of diabetes. Molecular docking studies, molecular dynamic simulations, and protein ligand interaction analysis were also performed for the newly synthesized compounds to investigate their predicted binding pattern and energies in PPARɣ binding site.

A Network Pharmacology Approach to Understand the Action Mechanisms of the TangShenKangPing Decoction for Diabetic Nephropathy Treatment

ABSTRACT Background: TangShenKangPing decoction (TSKPD) has been used to treat patients with diabetic nephropathy (DN) for more than 10 years. However, its active ingredients and their pharmacological mechanisms of action remain unclear. In this study, we aimed to identify the key targets, major active ingredients, and pathways of TSKPD using network pharmacology. Methods: Human phenotypic disease, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed and 37 candidates targets of 40 active TSKPD ingredients were identified. Enrichment analyses revealed that TSKPD reduced podocyte apoptosis via vitamin metabolic processes, regulated the inflammatory response via the advanced glycation end product–receptor for AGE (AGE-RAGE) signaling, and reduced abnormal angiogenesis via vascular endothelial growth factor (VEGF) signaling in patients with DN. Furthermore, we verified the therapeutic roles and action mechanism of TSKPD in db/db mice with DN. The medicine was administered via gavage for 12 weeks. Fasting blood glucose, blood lipid, pro-inflammatory cytokine, and 24 h urinary albumin levels and pathological alterations in the renal tissues were evaluated. KHDRBS1, NLRP3 and VEGF relative mRNA and protein expression levels in renal tissues were determined using reverse transcription-quantitative olymerase chain reaction (RT-qPCR) and western blotting, respectively. Results: Treatment with TSKPD decreased proteinuria and lipid levels in the serum, significantly decreased the kidney weight, ameliorated renal histopathological alterations, and reduced pro-inflammatory cytokine expression and oxidative stress in db/db mice. Conclusion: TSKPD exerts therapeutic effects by regulating multiple factors, reducing oxidative stress and inflammation, and protecting the podocytes.

Glutamine Defended the Kidneys Versus Lead Intoxication Via Elevating Endogenous Antioxidants, Reducing Inflammation and Carbonyl Stress, as well as Improving Insulin Resistance and Dyslipidemia.

Kidneys are primarily sensitive to lead (Pb) poisoning due to their cardinal role in lead excretion. Then, we studied the effect of glutamine (Gln) on lead nephrotoxicity in rats by assessing the histopathological and biochemical parameters (the renal NF-kβ expression, metabolic profile, oxidative stress, inflammatory markers, methylglyoxal (MGO), and glyoxalase-I activity). Forty rats were allotted into four groups (ten rats in each): normal (N), Gln-treated N, Pb intoxication (Pbi), and Gln-treated Pbi. The treated groups took 0.1% Gln in drinking water for 1 month. To motivate lead poisoning, rats gained 50 mg/l lead acetate in drinking water for 1 month. Oxidative stress indices (total glutathione, its reduced and oxidized forms, their ratios, advanced protein oxidation products, malondialdehyde, and ferric ion reducing power) and inflammatory markers (renal nuclear factor-kβ expression, interleukin 1β level, and myeloperoxidase activity) were measured. Furthermore, metabolic profile (fasting blood sugar, insulin, insulin resistance, lipid profile, and atherogenic index) and renal dysfunction parameters were determined. Pb-induced renal histopathological alterations were investigated by a pathologist. In the kidney of Pbi rats, the glomerulus was damaged. Gln prevented kidney damage and reduced kidney dysfunction parameters. In addition, Gln decreased oxidative stress and inflammation in sera and kidney homogenates. In addition, it improved insulin resistance, dyslipidemia, and carbonyl stress (p < 0.001). Gln guarded the kidneys versus lead intoxication by improving insulin resistance and dyslipidemia, elevating antioxidant markers, and diminishing inflammation and carbonyl stress.

Nano Diosgenin Abates DMBA Induced Renal and Hepatic Toxicities: Biochemical and Histopathological Evaluation on the Breast Cancer Model

Background: : Nature-based pharmaceuticals are now becoming an integral aspect of toxic-free healthcare therapies. Diosgenin (DN), a unique phyto steroidal sapogenin, seems to be explicitly employed as a core ingredient in countless traditional and patented Chinese medicines owing to its epic multilayered therapeutic treasure. Objective: The prime intent of the current study was to probe the hepato- and nephro- ameliorating impact of Diosgenin encapsulated chitosan nanoparticles (DN@CS-NPS) on 7,12-dimethylbenz(a)anthracene (DMBA) mediated rat mammary oncogenesis. Methods: A single dosage of DMBA (25 mg/kg body weight) was injected to induce breast cancer. Oral administration of DN (10 mg/kg body weight) and DN@CS-NPS (5 mg/kg body weight) was used to medicate DMBA administeredtumor-bearing rats just after the emergence of a tumor. Following the experimental duration, biochemical and histopathological (H&amp;E) analyses have been carried out. Results: Here, we noticed that there is an escalated level of liver and kidney biomarkers, phase-I detoxification enzymes, lipid peroxidative marker, total cholesterol (TC), phospholipids (PL), triglycerides (TG), and free fatty acids (FFA), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), total lipase (TL) as well as diminished levels of phase – II detoxification enzymes, enzymatic and non-enzymatic antioxidants, high-density lipoprotein (HDL), lipoprotein lipase (LPL) and lecithin acyltransferase (LCAT) in the plasma, liver and kidney tissues of DMBA-induced rats with renal and hepatic histopathological alterations. Conversely,oral treatment of DN@CS-NPS substantially reduced their tiers to near-normal levels. Conclusion: Thus, our observations suggested that DN@CS-NP is an impactful hepato- and nephro- therapeutic agent that might have a significant influence on breast cancer overfree DN.

Exploring the effects of edaravone in rats with contrast-induced acute kidney injury

AimsOxidative stress and inflammatory response play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). This study investigated the effects of edaravone in rats with CI-AKI. Main methodsMale Sprague Dawley rats were randomly assigned into four groups (n = 11–14/group): control, edaravone (30 mg/kg/day intraperitoneally (IP)), CI-AKI, and edaravone with CI-AKI. The induction of CI-AKI was performed by dehydration and the administration of contrast media (iohexol) and inhibitors of prostaglandin (indomethacin) and nitric oxide synthesis (L-NAME: N-nitro L-arginine methyl ester). Edaravone was administered for two weeks before the induction of CI-AKI. Serum creatinine and urea, renal oxidative stress and inflammatory biomarkers, and histopathological alterations were evaluated after 48 h of contrast exposure. Key findingsRats with CI-AKI showed a significant increase in serum creatinine and urea. The levels of antioxidant biomarkers including glutathione peroxidase, superoxide dismutase and reduced glutathione were significantly decreased in CI-AKI group versus control. Pre-treatment of rats with edaravone normalized kidney function and protected the kidney from oxidative damage as demonstrated by normalization of previous biomarkers. Furthermore, edaravone partially ameliorated renal histopathological alterations relative to the CI-AKI group, notably in the nephrons. No changes were observed in inflammatory biomarkers including tumour necrosis factor-alpha and interleukin-6 among all groups. SignificanceThe current findings suggest that edaravone could be a potential strategy to ameliorate developing CI-AKI possibly by improving renal antioxidant capacity. Further studies are warranted to expand the current understanding of the use of edaravone in the various models of AKI.

Renoprotective Effect of Pediococcus acidilactici GKA4 on Cisplatin-Induced Acute Kidney Injury by Mitigating Inflammation and Oxidative Stress and Regulating the MAPK, AMPK/SIRT1/NF-κB, and PI3K/AKT Pathways.

Acute kidney injury (AKI) describes a sudden loss of kidney function and is associated with a high mortality. Pediococcus acidilactici is a potent producer of bacteriocin and inhibits the growth of pathogens during fermentation and food storage; it has been used in the food industry for many years. In this study, the potential of P. acidilactici GKA4 (GKA4) to ameliorate AKI was investigated using a cisplatin-induced animal model. First, mice were given oral GKA4 for ten days and intraperitoneally injected with cisplatin on the seventh day to create an AKI mode. GKA4 attenuated renal histopathological alterations, serum biomarkers, the levels of inflammatory mediators, and lipid oxidation in cisplatin-induced nephrotoxicity. Moreover, GKA4 significantly decreased the expression of inflammation-related proteins and mitogen-activated protein kinase (MAPK) in kidney tissues. Eventually, GKA4 also increased the levels of related antioxidant enzymes and pathways. Consistently, sirtuin 1 (SIRT1) upregulated the level of autophagy-related proteins (LC3B, p62, and Beclin1). Further studies are needed to check our results and advance our knowledge of the mechanism whereby PI3K inhibition (wortmannin) reverses the effect of GKA4 on cisplatin-treated AKI. Taken together, GKA4 provides a therapeutic target with promising clinical potential after cisplatin treatment by reducing oxidative stress and inflammation via the MAPK, AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axes.

Epigallocatechin-3-gallate ameliorates renal endoplasmic reticulum stress-mediated inflammation in type 2 diabetic rats.

Epigallocatechin-3-gallate (EGCG), an essential polyphenolic constituent found in tea leaves, possesses various potent biological activities. This research was undertaken to investigate the impact of EGCG against endoplasmic reticulum (ER) stress-mediated inflammation and to clarify the underlying molecular mechanism in type 2 diabetic kidneys. The male rats were randomized into four groups: normal, diabetic, low-dose EGCG, and high-dose EGCG. In type 2 diabetic rats, hyperglycemia and hyperlipidemia noticeably caused renal structural damage and dysfunction and aggravated ER stress. Meanwhile, sustained ER stress activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and then upregulated the contents of inflammatory cytokines in the diabetic kidney. Following supplementation with 40 mg/kg and 80 mg/kg EGCG, hyperglycemia, hyperlipidemia, and renal histopathological alterations and dysfunction were noticeably ameliorated; renal ER stress, NLRP3 inflammasome, and inflammatory response were markedly repressed in the EGCG treatment groups. In summary, the current study highlighted the renoprotective effects of EGCG in type 2 diabetes and its mechanisms are mainly associated with the repression of ER stress-mediated NLRP3 inflammasome overactivation.

1,8 cineole protects type 2 diabetic rats against diabetic nephropathy via inducing the activity of glyoxalase-I and lowering the level of transforming growth factor-1β.

Diabetes leading to the production and circulation of glycation products along with the reduction of the activity of glyoxalase-I (GLO-I) contribute to diabetic nephropathy. Therefore, we studied the effect of 1,8 cineole (Cin) on the formation of diverse glycation products and the activity of GLO-I as well as renal histopathological alterations in the type-2 diabetic rat. Type 2 diabetes was induced in rats with a combination of streptozotocin and nicotinamide (55 + 200mg/kg). Two groups of rats, normal and diabetic, were treated intragastrically with Cin (200mg/kg) once daily for 2months. Fasting blood sugar, insulin resistance index, lipid profile, the activity of GLO-I, glycation products (Glycated albumin, Glycated LDL, Methylglyoxal, and advanced glycation end products), and oxidative stress (Advanced oxidation protein products, malondialdehyde, oxidized LDL, and reduced glutathione), inflammatory markers (Tumor necrosis factor-α and Transforming growth factor-1β), creatinine in the serum (Cre), and proteinuria (PU) in the urine of all rats was determined as well as renal histopathological alterations were investigated. Cin reduced biochemical (Cre and PU) and histopathological (glomerulosclerosis) indicators of renal dysfunction in the diabetic rat compared to untreated diabetic rats. Moreover, the treatment decreased different glycation, oxidative stress, and pro-inflammatory markers (p < 0.001).Further, Cin had an advantageous effect on glucose and lipid metabolism. Cin ameliorated diabetic nephropathy via reduction of TGF-1β following to decrease the formation of different glycation products, oxidative stress, and inflammatory process with the induction of the activity of glyoxalase-I in type 2 diabetic rats.

Adaptive Mechanisms of Renal Bile Acid Transporters in a Rat Model of Carbon Tetrachloride-Induced Liver Cirrhosis.

Background: Acute kidney injury (AKI) is common in advanced liver cirrhosis, a consequence of reduced kidney perfusion due to splanchnic arterial vasodilation and intrarenal vasoconstriction. It clinically manifests as hepatorenal syndrome type 1, type 2, or as acute tubular necrosis. Beyond hemodynamic factors, an additional mechanism may be hypothesized to explain the renal dysfunction during liver cirrhosis. Recent evidence suggest that such mechanisms may be closely related to obstructive jaundice. Methods: Given the not completely elucidated role of bile acids in kidney tissue damage, this study developed a rat model of AKI with liver cirrhosis induction by carbon tetrachloride (CCl4) inhalation for 12 weeks. Histological analyses of renal and liver biopsies were performed at sacrifice. Organic anion tubular transporter distribution and apoptosis in kidney cells were analyzed by immunohistochemistry. Circulating and urinary markers of inflammation and tubular injury were assayed in 21 treated rats over time (1, 2, 4, 8, and 12 weeks of CCl4 administration) and 5 controls. Results: No renal histopathological alterations were found at sacrifice. Comparing treated rats with controls, organic anion transporters were differentially expressed and localized. High serum bile acid values were detected in cirrhotic animals, while caspase-3 staining was negative in both groups. Increased levels of serum inflammatory and urinary tubular injury biomarkers were observed during cirrhosis progression, with a peak after 4 and 8 weeks of treatment. Conclusions: These findings suggest possible adaptive tubular mechanisms for bile acid transporters in response to cirrhosis-induced AKI.

Effect of Erythropoietin on Cisplatin Induced Nephrotoxicity in Adult Male Albino Rat: Histological, Ultrastructural and Biochemical Study

Introduction: Cisplatin is documented as an effective chemotherapeutic drug with many adverse effects on vital organs, including nephrotoxicity, neurotoxicity and ototoxicity. Erythropoietin is a glycoprotein hormone synthesized by the renal fibroblasts in the interstitial tissue of the renal cortex in response to hypoxia. Recent research work points out that it could to improve the renal dysfunction and histopathological alterations caused by oxidative stress. Aim of work: is to examine the possible protective role of erythropoietin in cases with cisplatin induced nephrotoxicity. Material and method: The present study used fifty adult male albino rats, with their weights within the range of 180-220 g. The rats were divided into five groups: Group I: received a single intraperitoneal injection of a normal saline solution. Group II: injected once with cisplatin intaperitoneally at a dose of 6 mg/kg. Group III: injected with a single dose of erythropoietin; 3000 IU/ kg intaperitoneally, and one day later they were injected with 6 mg/kg of cisplatin intaperitoneally. Group IV: injected with a single dose of erythropoietin; 3000 IU/kg intaperitoneally together with 6 mg/kg of cisplatin. Group V: injected with 3000 IU/kg erythropoietin intaperitoneally, and five days later they were given 6 mg/kg of cisplatin. Results: Cisplatin injection exerted various histopathological and laboratory alterations such as renal tubular cell necrosis, nuclear pyknosis and cytoplasmic vacuolation as well as marked elevation of levels of blood urea and serum creatinine. Erythropoietin could improve all the histopathological and functional deterioration exerted by cisplatin injection especially when given prior to cisplatin administration.

Evaluation of coenzyme Q10 combined with or without N-acetyl cysteine or atorvastatin for preventing contrast-induced kidney injury in diabetic rats.

Combined antioxidants effect for prevention of contrast-induced nephropathy (CIN) remains unclear. This study assessed the potential protective effects of coenzyme Q10 (CoQ10) alone or combined with N-acetyl cysteine (NAC) or atorvastatin against CIN in diabetic rats. Animals were randomly divided into five groups, including control and four disease groups with CIN and diabetes. Group 2 included diabetic rats with CIN. Groups 3-5 included diabetic rats that received CoQ10, CoQ10 and NAC, or CoQ10 and atorvastatin, respectively, before CIN induction. Serum, urine, and tissue were collected to evaluate renal protective effects of tested agents. Renal biomarkers, oxidative stress, and histopathological alterations were investigated. Rats with CIN showed significant renal impairment as revealed by the deleterious effects on kidney function and histology. While induction of CIN did not affect the renal levels of catalase, glutathione peroxidase (GPx), and thiobarbituric acid reactive substances, pretreatment of animals with CoQ10/NAC showed significant increase in GPx and catalase levels versus controls. Lastly, pretreatment with CoQ10/atorvastatin showed regenerative effect on distal tubules with mild kidney histology alterations relative to CIN rats. The combined use of CoQ10/atorvastatin could be a potential strategy to prevent CIN. However, future studies are warranted to test different combinations for longer prophylactic periods.

Dasatinib mitigates renal fibrosis in a rat model of UUO via inhibition of Src/STAT-3/NF-κB signaling

This research aimed to investigate the reno-protective impact of the tyrosine kinase inhibitor dasatinib (DAS) against renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats. DAS administration improved renal function and mitigated renal oxidative stress with paralleled reduction in the ligated kidney mass index, significant retraction in renal histopathological alterations and suppression of renal interstitial fibrosis. Nevertheless, DAS administration attenuated renal expression of phosphorylated Src (p-Src), Abelson (c-Abl) tyrosine kinases, nuclear factor-kappaB (NF-κB) p65, and phosphorylated signal transducer and activator of transcription-3 (p-STAT-3)/STAT-3 with paralleled reduction in renal contents of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). DAS diminished interstitial macrophage infiltration and decreased renal profibrotic transforming growth factor-β1 (TGF-β1) levels and suppressed interstitial expression of renal α-smooth muscle actin (α-SMA) and fibronectin. Collectively, DAS slowed the progression of renal interstitial fibrosis, possibly via attenuating renal oxidative stress, impairing Src/STAT-3/NF-κB signaling, and reducing renal inflammation.

Pentoxifylline mitigates cholestasis-related cholemic nephropathy

Aim of the studyCholestasis is the stoppage of bile flow that primarily affects liver function. On the other hand, kidneys are also severely influenced during cholestasis. Cholestasis-induced kidney injury is known as cholemic nephropathy (CN). There is no precise pharmacological option in CN. Previous studies revealed that oxidative stress plays a crucial role in the pathogenesis of CN. On the other hand, the positive effects of pentoxifylline (PTX) against renal injury with different etiologies have been frequently reported. In the current study, the potential nephroprotective role of PTX in cholestasis-induced renal injury is investigated.Material and methodsBile duct ligated (BDL) rats were treated with PTX (10, 50, and 100 mg/kg), and renal markers of oxidative stress, urine level of inflammatory cytokines, as well as renal histopathological alterations were monitored.ResultsSignificant changes in oxidative stress markers were detected in the BDL group. On the other hand, it was found that PTX (10, 50, and 100 mg/kg) significantly ameliorated cholestasis-induced oxidative stress in renal tissue. Renal histopathological changes, including interstitial inflammation, tubular atrophy, fibrosis, and cast formation, were detected in the BDL rats. Moreover, urine pro-inflammatory cytokines [interleukin (IL)-1, IL-9, IL-18, tumor necrosis factor α (TNF-α), and interferon γ (INF-γ)] were significantly increased in the cholestatic animals. PTX (10, 50, and 100 mg/kg, 14 days) significantly ameliorated renal histopathological alterations and urine levels of inflammatory cytokines.ConclusionsThese data indicate a potential nephroprotective role for PTX in cholestasis. The effects of PTX on oxidative stress parameters and the inflammatory response could play a primary role in its renoprotective mechanisms.

Origanum vulgare L. leaf extract alleviates finasteride-induced oxidative stress in mouse liver and kidney

Objective: To investigate the hepatorenoprotective effects of Origanum vulgare L. against finasteride-induced oxidative injury in the liver and kidney of mice. Methods: Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI/MS) analysis was utilized to yield a fingerprint of Origanum vulgare polyphenolic constituents. Thirty BALB/c mice received 0.5 mL/day distilled water, finasteride (25 mg/kg/day for 10 d), and 100, 200, or 400 mg/kg/day finasteride + Origanum vulgare extract with 6 mice per group for five weeks. On day 36, liver and kidney function as well as pro- and antiinflammatory (IFN-γ, IL-12, IL-6, TNF-α, IL-1β, and IL-10) cytokines were measured. The total antioxidant status, nitric oxide (NO), and malondialdehyde levels as well as the activities of NO synthase and catalase were also evaluated. Histopathological study was conducted to assess the effect of Origanum vulgare extract on finasteride-induced renal and hepatic toxicities. Results: Twenty-five major polyphenolic compounds were identified in the Origanum vulgare extract by LC-ESI/MS. Origanum vulgare extract, especially at 200 and 400 mg/kg/day doses, significantly improved liver and kidney biochemical indices, decreased inflammatory cytokines, increased total antioxidant status and NO synthase and catalase activities, as well as decreased plasma NO and malondialdehyde levels in a dose-dependent manner as compared to the finasteride group. Histopathological results further confirmed the protective effect of Origanum vulgare extract. Conclusions: Origanum vulgare extract ameliorates finasteride-induced hepatic and renal biochemical and histopathological alterations, and restores antioxidant/oxidant balance.

Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury

Tramadol (TMDL) is an opioid analgesic widely administered for the management of moderate to severe pain. On the other hand, TMDL is commonly abused in many countries because of its availability and cheap cost. Renal injury is related to high dose or chronic administration of TMDL. No precise mechanism for TMDL-induced renal damage has been identified so far. The current study aimed to evaluate the potential role of oxidative stress and mitochondrial impairment in the pathogenesis of TMDL-induced renal injury. For this purpose, rats were treated with TMDL (40 and 80 ​mg/kg, i.p, 28 consecutive days). A significant increase in serum Cr and BUN was detected in TMDL groups. On the other hand, TMDL (80 ​mg/kg) caused a substantial increase in urine glucose, ALP, protein, and γ-GT levels. Moreover, urine Cr was significantly decreased in TMDL-treated rats (40 and 80 ​mg/kg). Renal histopathological alterations included inflammation, necrosis, and tubular degeneration in the kidney of TMDL-treated animals. Reactive oxygen species (ROS) formation, increased oxidized glutathione (GSSG), lipid peroxidation, and protein carbonylation was increased, whereas total antioxidant capacity and reduced glutathione levels were considerably decreased in TMDL groups. Significant mitochondrial impairment was also detected in the form of mitochondrial depolarization, adenosine-tri-phosphate (ATP) depletion, mitochondrial permeabilization, lipid peroxidation, and decreased mitochondrial dehydrogenase activity in the kidney of TMDL (80 ​mg/kg)-treated animals. These data suggest mitochondrial impairment and oxidative stress as mechanisms involved in the pathogenesis of TMDL-induced renal injury.

Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function

Background and aimCholestasis-associated renal injury or cholemic nephropathy (CN) is a serious clinical problem. Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN. There is no specific pharmacological intervention for CN. Metformin is an anti-diabetic drug administered for decades. On the other hand, novel pharmacological properties have emerged for this drug. The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models. It has also been found that metformin positively affected mitochondrial function. The current study aimed to evaluate the effects of metformin in an animal model of CN. MethodsRats underwent bile duct ligation (BDL) and were treated with metformin (250 and 500 mg/kg) for 14 consecutive days. Two weeks after the BDL operations, urine, serum, and kidney samples were collected and analyzed. ResultsMarkers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, depleted antioxidant capacity, and decreased glutathione (GSH) levels were detected in BDL animals. Moreover, mitochondrial indices, including adenosine triphosphate (ATP) level, dehydrogenase activity, mitochondrial membrane potential, and mitochondrial permeability, were impaired in the kidney of cholestatic rats. Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation, cast formation, and fibrosis. It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats. Tissue histopathological alterations were also mitigated in metformin-treated groups. ConclusionsMetformin could be a candidate for managing CN. The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.

Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice

Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many other functions including the regulation of cell proliferation, inflammatory response, and glucose and lipid metabolism. In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity in mice. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α‑carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory gene expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways, especially the PI3K/AKT pathway. In vitro study further revealed that PXR protected against cisplatin-induced apoptosis of cultured proximal tubule cells in a PI3K-dependent manner. Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel protective target for cisplatin-induced nephrotoxicity.

Effects of Hesperetin on the Serum Superoxide Dismutase, Glutathione Peroxidase, and Malondialdehyde Levels and Renal-Histopathological Alterations Following Skeletal Muscle Ischemia Reperfusion in Male Rats

Objectives: The aim of the current study was to assess the effects of hesperetin on damage to kidneys as remote organs following skeletal muscle ischemia-reperfusion (IR) in rats. Materials and Methods: In general, 30 male Wistar rats were randomized and placed into sham, IR, hesperetin, dimethyl sulfoxide (DMSO), and IR+hesperetin groups. The rats in the hesperetin and IR+hesperetin groups received a 50 mg/kg dose of hesperetin dissolved in DMSO intraperitoneally. In the IR+hesperetin group, hesperetin was injected exactly prior to reperfusion. To induce skeletal muscle ischemia, the femoral artery was clamped for two hours. Following a 24-hour period of reperfusion, the samples of blood were collected for renal function tests and oxidative stress measurements. Next, the rats were euthanized, and histological analyses were conducted on their removed kidneys. Results: Based on the results, urea and creatinine serum levels were significantly higher in the IR group (P&lt;0.05) whereas they significantly reduced following treatment with hesperetin (P&lt;0.05). The concentration of malondialdehyde (P&lt;0.05) increased for the IR group while those of superoxide dismutase (P&lt;0.05) and glutathione peroxidase (P&lt;0.05) activities were lower than the other groups. The analysis of renal tissues in the IR group showed glomerular necrosis, degeneration, and necrosis of the tubular epithelium, protein casts, interstitial edema, and inflammation. Finally, the degree of renal injury was significantly ameliorated (P&lt;0.05) in rats treated with hesperetin. Conclusions: Overall, the results indicated that in rats, hesperetin could reduce renal injury that has been induced through skeletal muscle IR.

Carnosine Mitigates Biomarkers of Oxidative Stress, Improves Mitochondrial Function, and Alleviates Histopathological Alterations in the Renal Tissue of Cholestatic Rats

Background: Cholestatic liver disease primarily affects hepatic tissue. Cholestasis could also influence the function of other organs rather than the liver. Cholestasis-induced kidney injury is a severe clinical complication known as "cholemic nephropathy" (CN). Bile duct ligation (BDL) is a trustworthy experimental model for inducing CN. Although the precise mechanism of renal injury in cholestasis is not fully recognized, several studies revealed the role of oxidative stress in CN. There is no promising pharmacological intervention against CN. Carnosine (CAR) is a peptide extensively investigated for its pharmacological effects. Radical scavenging and antioxidative stress are major features of CAR. The current study aimed to evaluate the role of CAR supplementation on the CN. Methods: CAR was administered (250 and 500 mg/kg, i.p) to BDL rats for 14 consecutive days. Urine and serum markers of renal injury, biomarkers of oxidative stress in the kidney tissue, and renal histopathological alterations were monitored. Results: Significant elevation in oxidative stress biomarkers, including ROS formation, lipid peroxidation, oxidized glutathione (GSSG) levels, and protein carbonylation were found in the kidney of BDL rats. Moreover, renal tissue antioxidant capacity and reduced glutathione (GSH) levels were significantly decreased in the organ of cholestatic animals. Renal histopathological changes, including tubular atrophy, interstitial inflammation, tissue fibrosis, and cast formation, were detected in the kidney of BDL rats. It was found that CAR administration significantly protected the kidney of cholestatic animals. Conclusion: The antioxidative properties of this peptide might play a fundamental role in its protective properties during cholestasis.

Protective Effect of Earthworms (Pheretima hawayana Rosa and Allolobophora caliginosa Savigny) Methanolic Extract on Acrylamide Induced Hepatorenal Toxicity

The present study was carried out to evaluate the protective potentials of earthworm extract (EE) against acrylamide-induced hepatorenal toxicity. Forty rats were randomly divided into 4 groups (n=10). G І (control): were received distilled water (D.W); G ІІ: rats were administered acrylamide (ACR; 5 mg/kg B.W in D.W) orally for 3 weeks; G ІІІ: rats were given EE (300 mg/kg B.W in D.W) orally for 3 weeks; G ІV: rats were pretreated with EE for 3 weeks, then co-treated by EE and ACR for an additional 3 weeks. The results showed that acrylamide increased serum ALT, AST, total bilirubin, urea, and creatinine, while decreased albumin and total proteins. Acrylamide resulted in congestion of central veins and hepatic sinusoids, and hydropic degeneration of most hepatocytes. Also, ACR caused inflammatory cells infiltration in hepatic sinusoids and areas of coagulative necrosis infiltrated by inflammatory cells. Furthermore, ACR lead to alteration in kidney tissue via shrinkage of glomerular tuft with increased Bowman's space. Also, ACR lead to congestion and inflammatory cells infiltration of interstitial tissue, renal tubules with desquamated renal epithelium in their lumen forming epithelial casts. Acrylamide caused degenerative changes of some epithelial cells lining the renal tubules, other cells showed necrosis. EE recovered hepatic and renal histopathological and biochemical alterations induced by ACR. In Conclusion: Earthworm extract ameliorated acrylamide-induced hepatorenal toxicity.