Protective effect of coenzyme Q10 in cyclophosphamide-induced kidney damage in rats.

OBJECTIVE: We aimed to investigate the effect of coenzyme q10 on cyclophosphamide-induced kidney damage in rats. METHODS: A total of 30 female Wistar-Albino rats were utilized to form three groups. In group 1 (control group) (n=10), no drugs were given. In group 2 (cyclophosphamide group) (n=10), 30 mg/kg intraperitoneal cyclophosphamide was administered for 7 days. In group 3 (cyclophosphamide+coenzyme q10 group) (n=10), 30 mg/kg cyclophosphamide and 10 mg/kg coenzyme q10 were given for 7 days via intraperitoneal route. Right kidneys were removed in all groups. Blood malondialdehyde levels and activities of catalase and superoxide dismutase were measured. Histopathological damage was evaluated by examining the slides prepared from kidney tissue using a light microscope. RESULTS: Tissue damage was significantly higher in the cyclophosphamide group than in the cyclophosphamide+coenzyme q10 group (p<0.05). The malondialdehyde levels were significantly higher and the activities of superoxide dismutase and catalase were lower in the cyclophosphamide group than in the cyclophosphamide+coenzyme q10 group (p<0.05). CONCLUSION: Coenzyme q10 may be a good option to prevent cyclophosphamide-induced kidney damage.

Dysregulation of ferroptosis may participate in the mitigating effect of CoCl2 on contrast-induced nephropathy.

BACKGROUND: Contrast agents can directly or indirectly induce renal tubular ischemia and hypoxic damage. Given that cobalt chloride (CoCl2) can protect renal tubules, the protective effect and potential mechanism of action of CoCl2 on contrast-induced nephropathy (CIN) warrant investigation. METHODS: A CIN mouse model was established to determine the protective effect of CoCl2 on renal injury in vivo. Then, TMT-based proteomics was performed to determine the differentially expressed proteins (DEPs), following which, enrichment analyses of gene ontology and the KEGG pathway were performed. In vitro, a CIN model was constructed with renal tubular epithelial cells (HK-2) to determine the effect of CoCl2 on potential targets and the role of the key protein identified from the in vivo experiments. RESULTS: CoCl2 treatment decreased the levels of BUN and serum creatinine (sCr), while increasing the levels of urea and creatinine (Cr) in the urine of mice after CIN injury. Damage to the renal tubules in the CoCl2 treatment group was significantly less than in the CIN model group. We identified 79 DEPs after treating the in vivo model with CoCl2, and frequently observed ferroptosis-related GO and KEGG pathway terms. Of these, Hp (haptoglobin) was selected and found to have a strong renoprotective effect, even though its expression level in kidney tissue decreased after CoCl2 treatment. In HK-2 cells, overexpression of Hp reduced the ferroptosis caused by erastin, while knocking down Hp negated the attenuation effect of CoCl2 on HK-2 cell ferroptosis. CONCLUSION: CoCl2 attenuated kidney damage in the CIN model, and this effect was associated with the decrease in ferroptosis mediated by Hp.

Thymoquinone: An Effective Natural Compound for Kidney Protection.

Kidney disease is a common health problem worldwide. Acute or chronic injuries may interfere with kidney functions, eventually resulting in irreversible kidney damage. A number of recent studies have shown that the plant-derived natural products have an extensive potential for renal protection. Thymoquinone (TQ) is an essential compound derived from Nigella Sativa (NS), which is widely applied in the Middle East as a folk medicine. Previous experiments have demonstrated that TQ has a variety of potential pharmacological effects, including anti-oxidant, antibacterial, antitumor, immunomodulatory, and neuroprotective activities. In particular, the prominent renal protective efficacy of TQ has been demonstrated in both in vivo and in vitro experiments. TQ can prevent acute kidney injuries from various xenobiotics through anti-oxidation, anti-inflammatory, and anti-apoptosis effects. In addition, TQ exhibited significant pharmacological effects on renal cell carcinoma, renal fibrosis, and urinary calculi. The essential mechanisms involve scavenging ROS and increasing anti-oxidant activity, decreasing inflammatory mediators, inducing apoptosis, and inhibiting migration and invasion. The purpose of this review is to conclude the pharmacological effects and the potential mechanisms of TQ in renal protection, shedding new light on the exploration of medicinal phyto-protective agents targeting kidneys.

Mitochondrial SIRT3 as a protective factor against cyclosporine A-induced nephrotoxicity.

Sirtuin3 (SIRT3), a mitochondrial deacetylase, has been shown to be involved in various kidney diseases. In this study, we aimed to clarify the role of SIRT3 in cyclosporine-induced nephrotoxicity and the associated mitochondrial dysfunction. Madin-Darby canine kidney (MDCK) cells were transfected with Flag-tagged SIRT3 for SIRT3 overexpression or SIRT3 siRNA for the inhibition of SIRT3. Subsequently, the cells were treated with cyclosporine A (CsA) or vehicle. Wild-type and SIRT3 knockout (KO) mice were randomly assigned to receive cyclosporine A or olive oil. Furthermore, SIRT3 activator, honokiol, was treated alongside CsA to wild type mice. Our results revealed that CsA treatment inhibited mitochondrial SIRT3 expression in MDCK cells. Inhibition of SIRT3 through siRNA transfection exacerbated apoptosis, impaired the expression of the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK-PGC1α) pathway, and worsened mitochondrial dysfunction induced by CsA treatment. Conversely, overexpression of SIRT3 through Flag-tagged SIRT3 transfection ameliorated apoptosis, increased the expression of mitochondrial superoxide dismutase 2, and restored the mitochondrial regulator pathway, AMPK-PGC1α. In SIRT3 KO mice, CsA treatment led to aggravated kidney dysfunction, increased kidney tubular injury, and accumulation of oxidative end products indicative of oxidative stress injury. Meanwhile, SIRT3 activation in vivo significantly mitigated these adverse effects, improving kidney function, reducing oxidative stress markers, and enhancing mitochondrial health following CsA treatment. Overall, our findings suggest that SIRT3 plays a protective role in alleviating mitochondrial dysfunction caused by CsA through the activation of the AMPK-PGC1α pathway, thereby preventing further kidney injury.

Pharmacodynamic Evaluation and Mechanism of Ginseng Polysaccharide against Nephrotoxicity Induced by Hexavalent Chromium.

Hexavalent chromium is a common pollutant in the environment. Long-term exposure to hexavalent chromium can cause damage to multiple organs. The kidney is one of the main organs that metabolizes heavy metal toxicity, and the accumulation of Cr (VI) in the body can lead to serious damage to kidney function. Studies have shown that ginseng polysaccharides have the function of preventing cisplatin-induced endoplasmic reticulum stress, inflammatory response, and apoptosis in renal cells, but their efficacy and mechanisms against hexavalent chromium-induced nephrotoxicity need to be explored. The aim of this study was to explore the efficacy and mechanism of ginseng polysaccharide against hexavalent chromium-induced nephrotoxicity. The results of pharmacodynamic experiments showed that ginseng polysaccharide could significantly reduce the kidney index, urea nitrogen (BUN), and serum creatinine (Cre) values of K2Cr2O7-treated mice. The results of mechanistic experiments showed that ginseng polysaccharides could alleviate oxidative stress, apoptosis, and biofilm damage in renal tissues caused by Cr (VI). Lipidomic correlation analysis showed that ginseng polysaccharides could protect the organism by regulating the expression of differential lipids. This study opens new avenues for the development of alternative strategies for the prevention of kidney injury caused by hexavalent chromium.

Kokusaginine attenuates renal fibrosis by inhibiting the PI3K/AKT signaling pathway.

Kokusaginine is an active ingredient alkaloid that has been isolated and extracted from Ruta graveolens L. Some researches have indicated that alkaloids possess anti-inflammatory and antioxidant effects. Nevertheless, the potential nephroprotective effects of kokusaginine on renal fibrosis remain undetermined. This study was conducted to examine the protective effect of kokusaginine on renal fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. Renal fibrosis was induced in male C57BL/6 J mice by feeding with 0.2% adenine-containing food and UUO surgery. Kokusaginine was administered orally simultaneously after the establishment of renal fibrosis. Renal function was measured by serum levels of creatinine and urea nitrogen. Renal pathological changes were assessed by HE staining and Masson staining. Western blotting was employed to detect the expression levels of fibrosis-related proteins in mice and cells. Additionally, network pharmacology analysis and RNA-seq were utilized to predict the pathways through which kokusaginine could exert its anti-fibrotic effects. The treatment with kokusaginine enhanced renal function, alleviated renal histoarchitectural lesions, and mitigated renal fibrosis in the renal fibrosis models. The network pharmacology and RNA-seq enrichment analysis of the KEGG pathway demonstrated that kokusaginine could exert anti-renal fibrosis activity via the PI3K/AKT signaling pathway. And the results were verified in both in vitro and in vivo experiments. In conclusion, our data implied that kokusaginine inhibited the activation of the PI3K/AKT signaling pathway both in vitro and in vivo, and suppressed the formation of renal fibrosis. Thus, the kokusaginine-mediated PI3K/AKT signaling pathway may represent a novel approach for the treatment of renal fibrosis.

The potential role of Tirzepatide as adjuvant therapy in countering colistin-induced nephro and neurotoxicity in rats via modulation of PI3K/p-Akt/GSK3-ß/NF-kB p65 hub, shielding against oxidative and endoplasmic reticulum stress, and activation of p-CREB/BDNF/TrkB cascade.

Although colistin has a crucial antibacterial activity in treating multidrug-resistant gram-negative bacteria strains; it exhibited renal and neuronal toxicities rendering its use a challenge. Previous studies investigated the incretin hormones either glucose-dependent insulinotropic polypeptide (GIP) or glucagonlike peptide-1 (GLP-1) for their neuroprotective and nephroprotective effectiveness. The present study focused on investigating Tirzepatide (Tirze), a dual GLP-1/GIP agonist, as an adjuvant therapy in the colistin treatment protocol for attenuating its renal and neuronal complications. Rats were divided into; The normal control group, the colistin-treated group received colistin (300,000 IU/kg/day for 7 days; i.p.). The Tirze-treated group received Tirze (1.35 mg/kg on the 1,4,7thdays; s.c.) and daily colistin. Tirze effectively enhanced histopathological alterations, renal function parameters, and locomotor activity in rats. Tirze mechanistically acted via modulating various signaling axes evolved under the insult of phosphatidylinositol 3-kinases (PI3K)/phosphorylated protein kinase-B (p-Akt)/ glycogen synthase kinase (GSK)3-ß hub causing mitigation of nuclear factor (NF)-κB (NF-κB) / tumor necrosis factor-α (TNF-α), increment of nuclear factor erythroid 2-related factor 2 (Nrf2)/ glutathione (GSH), downregulation of ER stress-related biomarkers (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)), antiapoptotic effects coupling with reduction of glial fibrillary acidic protein (GFAP) immunoreactivity and enhancement of phosphorylated c-AMP response element-binding (p-CREB) / brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) neuroprotective pathway. Briefly, Tirze exerts a promising role as adjuvant therapy in the colistin treatment protocol for protection against colistin's nephro- and neurotoxicity according to its anti-inflammatory, antioxidant, and antiapoptotic impacts besides its ability to suppress ER stress-related biomarkers.

Comparison of preventive effects of combined furosemide and mannitol versus single diuretics, furosemide or mannitol, on cisplatin-induced nephrotoxicity.

Cisplatin (CDDP)-induced nephrotoxicity is a common dose-limiting toxicity, and diuretics are often administered to prevent nephrotoxicity. However, the efficacy and optimal administration of diuretics in preventing CDDP-induced nephrotoxicity remain to be established. This study aimed to evaluate the efficacy of combining furosemide and mannitol to prevent CDDP-induced nephrotoxicity. This was a post-hoc analysis of pooled data from a multicenter, retrospective, observational study, including 396 patients who received one or two diuretics for CDDP-based chemotherapy, compared using propensity score matching. Multivariate logistic regression analyses were used to identify risk factors for nephrotoxicity. There was no significant difference in the incidence of nephrotoxicity between the two groups (22.2% vs. 28.3%, P = 0.416). Hypertension, CDDP dose ≥ 75 mg/m2, and no magnesium supplementation were identified as risk factors for nephrotoxicity, whereas the use of diuretics was not found to be a risk factor. The combination of furosemide and mannitol showed no advantage over a single diuretic in preventing CDDP-induced nephrotoxicity. The renal function of patients receiving CDDP-based chemotherapy (≥ 75 mg/m2) and that of those with hypertension should be carefully monitored. Magnesium supplementation is important for these patients.

Hesperidin alleviates zinc-induced nephrotoxicity via the gut-kidney axis in swine.

Introduction: Zinc (Zn) is an essential trace element in animals, but excessive intake can lead to renal toxicity damage. Thus, the exploration of effective natural antagonists to reduce the toxicity caused by Zn has become a major scientific problem. Methods: Here, we found that hesperidin could effectively alleviate the renal toxicity induced by Zn in pigs by using hematoxylin-eosin staining, transmission electron microscope, immunohistochemistry, fluorescence quantitative PCR, and microfloral DNA sequencing. Results: The results showed that hesperidin could effectively attenuate the pathological injury in kidney, and reduce autophagy and apoptosis induced by Zn, which evidenced by the downregulation of LC3, ATG5, Bak1, Bax, Caspase-3 and upregulation of p62 and Bcl2. Additionally, hesperidin could reverse colon injury and the decrease of ZO-1 protein expression. Interestingly, hesperidin restored the intestinal flora structure disturbed by Zn, and significantly reduced the abundance of Tenericutes (phylum level) and Christensenella (genus level). Discussion: Thus, altered intestinal flora and intestinal barrier function constitute the gut-kidney axis, which is involved in hesperidin alleviating Zn-induced nephrotoxicity. Our study provides theoretical basis and practical significance of hesperidin for the prevention and treatment of Zn-induced nephrotoxicity through gut-kidney axis.

Kefir mitigates renal damage caused by zearalenone in female wistar rats by reducing oxidative stress.

The estrogen-like mycotoxin zearalenone (ZEA) was popularly occurred in several food and feeds, posing threats to human and animal health. ZEA induced renal toxicity and caused oxidative stress. In the current study, the protecting effect of kefir administration against ZEA-induced renal damage in rats was explored. Rats were divided into 4 groups, each consisting of 5 animals. For the initial 7 days, they were orally administered sterile milk (200 µL/day). Subsequently, during the second week, the groups were exposed to kefir (200 µL/day), ZEA (40 mg/kg b.w./day) and a combination of kefir and ZEA. The biochemical parameters, kidney histological changes and ZEA residue were assessed. Kefir supplementation enhanced the antioxidant enzymes in the kidney, such as superoxide dismutase, catalase and glutathione peroxidase activities, which increased by 1.2, 4 and 20 folds, respectively, relative to the ZEA group. Remarkably, the concomitant administration kefir + ZEA suppressed ZEA residues in both serum and kidney. Additionally, serum levels of blood urea nitrogen, uric acid and renal malondialdehyde decreased by 22, 65 and 54%, respectively, in the kefir + ZEA group; while, the creatinine content increased by around 60%. Rats co-treated with kefir showed a normal kidney histological architecture contrary to tissues alterations mediated in the ZEA group. These results suggest that kefir may showed a protective effect on the kidneys, mitigating ZEA-induced acute toxicity in rats.

Effects of adenosine triphosphate, Lacidipine, and Benidipine on 5-fluorouracil-induced kidney damage in rats.

OBJECTIVE: In the present study, the protective effects of adenosine triphosphate (ATP), Benidipine, and Lacidipine on potential kidney damage induced by 5-fluorouracil (5-FU) were investigated in rats. MATERIALS AND METHODS: Totally 48 rats were divided into 8 groups: healthy (HG), 5-FU (FUG), ATP+5-FU (AFU), Benidipine+5-FU (BFU), Lacidipine+5-FU (LFU), ATP+Benidipine+5-FU (ABFU), ATP+Lacidipine+5-FU (ALFU) and Benidipine+Lacidipine+5-FU (BLFU). In a 10-day period, ATP (4 mg/kg) was administered intraperitoneally, and Benidipine (4 mg/kg) and Lacidipine (4 mg/kg) were administered orally once a day. On days 1, 3, and 5, 5-FU (100 mg/kg) was administered intraperitoneally one hour after the drug was administered. Afterward, the rats were euthanized, and kidney tissues were removed. An analysis of malondialdehyde, total glutathione, superoxide dismutase, and catalase was performed on tissues, as well as a histopathological examination. A creatinine and blood urea nitrogen analysis were performed on blood samples. RESULTS: It was revealed that 5-FU decreased the amount of total glutathione, superoxide dismutase, and catalase activities in rat kidney tissues and increased malondialdehyde. Further, increased serum creatinine and blood urea nitrogen levels, as well as histopathological examination of kidney tissues, were found in the 5-FU group. ATP+Benidipine and ATP treatments were the most effective in preventing both biochemical and histopathological changes induced by 5-FU. A treatment with Benidipine improved biochemical and histopathologic data, but not to the same extent as a treatment with ATP+Benidipine and ATP. As a result of Lacidipine+ATP combination, 5-FU-induced biochemical changes in kidney tissue were partially inhibited, but the degree of histopathologic damage remained unchanged. Neither Benidipine+Lacidipine nor Lacidipine showed a protective effect on both biochemical changes and histopathologic damage. CONCLUSIONS: It may be possible to prevent nephrotoxicity by adding ATP + Benidipine or ATP to 5-FU treatment.

Iguratimod prevents renal fibrosis in unilateral ureteral obstruction model mice by suppressing M2 macrophage infiltration and macrophage-myofibroblast transition.

Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-ß and iguratimod or SRC inhibitors in vitro, suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage-myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.

Ferulic acid alleviates avermectin induced renal injury in carp by inhibiting inflammation, oxidative stress and apoptosis.

Avamectin (AVM), a macrolide antibiotic, is widely used in fisheries, agriculture, and animal husbandry, however, its irrational use poses a great danger to aquatic organisms. Ferulic acid (FA) is a natural chemical found in the cell walls of plants. It absorbs free radicals from the surrounding environment and acts as an antioxidant. However, the protective effect of FA against kidney injury caused by AVM has not been demonstrated. In this study, 60 carp were divided into the control group, AVM group (2.404 µg/L), FA+AVM group and FA group (400 mg/kg). Pathological examination, quantitative real-time PCR (qPCR), reactive oxygen species (ROS) and western blot were used to evaluate the preventive effect of FA on renal tissue injury after AVM exposure. Histological findings indicated that FA significantly reduced the swelling and infiltration of inflammatory cells in the kidney tissues of carp triggered by AVM. Dihydroethidium (DHE) fluorescent probe assay showed that FA inhibited the accumulation of kidney ROS. Biochemical results showed that FA significantly increased glutathione (GSH) content, total antioxidant capacity (T-AOC) and catalase (CAT) activity, and decreased intracellular malondialdehyde (MDA) content. In addition, western blot results revealed that the protein expression levels of Nrf2 and p-NF-κBp65 in the carp kidney were inhibited by AVM, but reversed by the FA. The qPCR results exhibited that FA significantly increased the mRNA levels of tgf-ß1 and il-10, while significantly down-regulated the gene expression levels of tnf-α, il-6 and il-1ß. These data suggest that FA can reduce oxidative stress and renal tissue inflammation induced by AVM. At the same time, FA inhibited the apoptosis of renal cells induced by AVM by decreasing the transcription level and protein expression level of Bax, and increasing the transcription level and protein expression level of Bcl2, PI3K and AKT. This study provides preliminary evidence for the theory that FA reduces the level of oxidative stress, inflammation response and kidney tissue damage caused by apoptosis in carp, providing a theoretical basis for the prevention and treatment of the AVM.

Hydrangea paniculata coumarins alleviate adriamycin-induced renal lipotoxicity through activating AMPK and inhibiting C/EBPß.

ETHNOPHARMACOLOGICAL RELEVANCE: Throughout Chinese history, Hydrangea paniculata Siebold has been utilized as a traditional medicinal herb to treat a variety of ailments associated to inflammation. In a number of immune-mediated kidney disorders, total coumarins extracted from Hydrangea paniculata (HP) have demonstrated a renal protective effect. AIM OF THE STUDY: To investigate renal beneficial effect of HP on experimental Adriamycin nephropathy (AN), and further clarify whether reversing lipid metabolism abnormalities by HP contributes to its renoprotective effect and find out the underlying critical pathways. MATERIALS AND METHODS: After establishment of rat AN model, HP was orally administrated for 6 weeks. Biochemical indicators related to kidney injury were determined. mRNAs sequencing using kidney tissues were performed to clarify the underlying mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, western blot, molecular docking, and drug affinity responsive target stability (DARTS) assay was carried out to further explore and confirm pivotal molecular pathways and possible target by which HP and 7-hydroxylcoumarin (7-HC) played their renal protection effect via modulating lipid metabolism. RESULTS: HP could significantly improve renal function, and restore renal tubular abnormal lipid metabolism and interstitial fibrosis in AN. In vitro study demonstrated that HP and its main metabolite 7-HC could reduce ADR-induced intracellular lipid deposition and fibrosis characteristics in renal tubular cells. Mechanically, HP and 7-HC can activate AMP-activated protein kinase (AMPK) via direct interaction, which contributes to its lipid metabolism modulation effect. Moreover, HP and 7-HC can inhibit fibrosis by inhibiting CCAAT/enhancer binding protein beta (C/EBPß) expression in renal tubular cells. Normalization of lipid metabolism by HP and 7-HC further provided protection of mitochondrial structure integrity and inhibited the nuclear factor kappa-B (NF-κB) pathway. Long-term toxicity using beagle dogs proved the safety of HP after one-month administration. CONCLUSION: Coumarin derivates from HP alleviate adriamycin-induced lipotoxicity and fibrosis in kidney through activating AMPK and inhibiting C/EBPß.

Beclin-1-Derived Peptide MP1 Attenuates Renal Fibrosis by Inhibiting the Wnt/ß-Catenin Pathway.

Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix and progressive loss of nephron function, with a lack of effective treatment options in clinical practice. In this study, we discovered that the Beclin-1-derived peptide MP1 significantly inhibits the abnormal expression of fibrosis and epithelial-mesenchymal transition-related markers, including α-smooth muscle actin, fibronectin, collagen I, matrix metallopeptidase 2, Snail1, and vimentin both in vitro and in vivo. H&E staining was employed to evaluate renal function, while serum creatinine (Scr) and blood urea nitrogen (BUN) were used as main indices to assess pathologic changes in the obstructed kidney. The results demonstrated that daily treatment with MP1 during the 14-day experiment significantly alleviated renal dysfunction and changes in Scr and BUN in mice with unilateral ureteral obstruction. Mechanistic research revealed that MP1 was found to have a significant inhibitory effect on the expression of crucial components involved in both the Wnt/ß-catenin and transforming growth factor (TGF)-ß/Smad pathways, including ß-catenin, C-Myc, cyclin D1, TGF-ß1, and p-Smad/Smad. However, MP1 exhibited no significant impact on either the LC3II/LC3I ratio or P62 levels. These findings indicate that MP1 improves renal physiologic function and mitigates the fibrosis progression by inhibiting the Wnt/ß-catenin pathway. Our study suggests that MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis. SIGNIFICANCE STATEMENT: This study indicated that the Beclin-1-derived peptide MP1 effectively mitigated renal fibrosis induced by unilateral ureteral obstruction through inhibiting the Wnt/ß-catenin pathway and transforming growth factor-ß/Smad pathway, thereby improving renal physiological function. Importantly, unlike other Beclin-1-derived peptides, MP1 exhibited no significant impact on autophagy in normal cells. MP1 represents a promising and novel candidate drug precursor for the treatment of renal fibrosis focusing on Beclin-1 derivatives and Wnt/ß-catenin pathway.

Demethylzeylasteral protects against renal interstitial fibrosis by attenuating mitochondrial complex I-mediated oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Renal interstitial fibrosis (RIF) is a main pathological process in chronic kidney disease (CKD). Demethylzeylasteral (DML), a major component of Tripterygium wilfordii Hook. f., has anti-renal fibrosis effects. However, its mechanism of action remains incompletely understood. AIM OF THE STUDY: The present study was designed to comprehensively examine the effects of DML on RIF and the underlying mechanisms. MATERIALS AND METHODS: Pathological experiments were performed to determine the therapeutic effect of DML on a mouse model of UUO-induced RIF. To determine the novel mechanisms underlying the therapeutic effects of DML against RIF, a comprehensive transcriptomics analysis was performed on renal tissues, which was further verified by a series of experiments. RESULTS: Pathological and immunohistochemical staining showed that DML inhibited UUO-induced renal damage and reduced the expression of fibrosis-related proteins in mice. Transcriptomic analysis revealed that the partial subunits of mitochondrial complex (MC) I and II may be targets by which DML protects against RIF. Furthermore, DML treatment reduced mitochondrial reactive oxygen species (ROS) levels, consequently promoting ATP production and mitigating oxidative stress-induced injury in mice and cells. Notably, this protective effect was attributed to the inhibition of MC I activity, suggesting a crucial role for this specific complex in mediating the therapeutic effects of DML against RIF. CONCLUSIONS: This study provides compelling evidence that DML may be used to treat RIF by effectively suppressing mitochondrial oxidative stress injury mediated by MC I. These findings offer valuable insights into the pharmacological mechanisms of DML and its potential clinical application for patients with CKD.

Effect of modified citrus pectin on galectin-3 inhibition in cisplatin-induced cardiac and renal toxicity.

This study evaluated the effect of pharmacological inhibition of galectin 3 (Gal-3) with modified citrus pectin (MCP) on the heart and kidney in a model of cisplatin-induced acute toxicity. Male Wistar rats were divided into four groups (n = 6/group): SHAM, which received sterile saline intraperitoneally (i.p.) for three days; CIS, which received cisplatin i.p. (10 mg/kg/day) for three days; MCP, which received MCP orally (100 mg/kg/day) for seven days, followed by sterile saline i.p. for three days; MCP+CIS, which received MCP orally for seven days followed by cisplatin i.p. for three days. The blood, heart, and kidneys were collected six hours after the last treatment. MCP treatment did not change Gal-3 protein levels in the blood and heart, but it did reduce them in the kidneys of the MCP groups compared to the SHAM group. While no morphological changes were evident in the cardiac tissue, increased malondialdehyde (MDA) levels and deregulation of the mitochondrial oxidative phosphorylation system were observed in the heart homogenates of the MCP+CIS group. Cisplatin administration caused acute tubular degeneration in the kidneys; the MCP+CIS group also showed increased MDA levels. In conclusion, MCP therapy in the acute model of cisplatin-induced toxicity increases oxidative stress in cardiac and renal tissues. Further investigations are needed to determine the beneficial and harmful roles of Gal-3 in the cardiorenal system since it can act differently in acute and chronic diseases/conditions.