lignans and Kidney-Diseases

The plants of the genus Phyllanthus (Euphorbiaceae) are widely distributed in most tropical and subtropical countries, and have long been used in folk medicine to treat kidney and urinary bladder disturbances, intestinal infections, diabetes, and hepatitis B. In recent years, the interest in the plants has increased considerably. Substantial progress on their chemistal and pharmacological properties, as well as a few clinical studies of some Phyllanthus species have been made. This review discusses the current knowledge of their chemistry, the in vitro and in vivo pharmacological, biochemical, and clinical studies carried out on the extracts, and the main active constituents isolated from different species of plants of the genus Phyllanthus. These studies carried out with the extracts and purified compounds from these plants support most of their reported uses in folk medicine as an antiviral, in the treatment of genitourinary disorders, and as antinociceptive agents. However, well-controlled, double-binding clinical trials are lacking. Several compounds including alkaloids, flavonoids, lignans, phenols, and terpenes were isolated from these plants and some of them interact with most key enzymes. Together this data strongly supports the view that the plants belonging to the genus Phyllanthus have potential beneficial therapeutic actions in the management of hepatitis B, nefrolitiase, and in painful disorders.

Topics: Alkaloids; Analgesics; Animals; Antiviral Agents; Brazil; Diabetes Mellitus; Euphorbiaceae; Flavonoids; Hepatitis B; Humans; Intestinal Diseases; Kidney Diseases; Lignans; Medicine, Traditional; Phenols; Phytotherapy; Plant Extracts; Plants, Medicinal; Terpenes; Tropical Climate; Urinary Bladder Diseases

Nephrotoxicity is a critical consequence of cadmium toxicity. Cadmium induces nephrotoxicity through disruption of cellular redox balance and induction of endoplasmic reticulum stress (ERS) and inflammatory responses. The present study investigated the renoprotective effects of the naturally occurring arctigenin against the cadmium-induced nephrotoxicity.. Male Wistar rats were randomized into normal control, arctigenin control, cadmium, and cadmium/arctigenin groups. Cadmium and arctigenin were administered daily over a seven-day period. On the eighth day, blood and kidney tissue specimens were collected and subjected to spectrophotometric, ELISA, and immunoblotting analysis.. Arctigenin significantly improved renal functions and reduced renal tubular injury in the cadmium-intoxicated rats as reflected by increased GFR and reduced levels of serum creatinine, BUN, urinary albumin-to-creatinine ratio, and protein expression of KIM-1. Arctigenin alleviated the cadmium-induced oxidative DNA damage and lipid peroxidation while boosted reduced glutathione level and antioxidant enzymes activity. Mechanistically, arctigenin enhanced nuclear translocation of the antioxidant transcription factor Nrf2 and up-regulated its downstream redox-regulating enzymes HO-1 and NQO1. Importantly, arctigenin ameliorated the cadmium-evoked ERS as demonstrated by reduced protein expression of the key molecules Bip, PERK, IRE1α, CHOP, phspho-eIF2α, and caspase-12 and diminished activity of caspase-12. Additionally, arctigenin down-regulated the cadmium-induced NF-κB nuclear translocation and decreased its downstream pro-inflammatory cytokines TNF-α and IL-1β.. The current work underlines the alleviating activity of arctigenin against cadmium-evoked nephrotoxicity potentially through mitigating ERS and targeting Nrf2 and NF-κB signaling. The current findings support possible therapeutic application of arctigenin in controlling cadmium-induced nephrotoxicity although clinical investigations are necessary.

Topics: Animals; Cadmium; Endoplasmic Reticulum Stress; Furans; Inflammation Mediators; Kidney Diseases; Lignans; Male; NF-E2-Related Factor 2; Rats, Wistar

Nephrotoxicity of cisplatin (CP) involves renal oxidative stress and inflammation, and sesamin (a major liganin in many plants) has strong antioxidant and antiinflammatory actions. Therefore, we investigated here the possible mitigative action of sesamin on CP nephrotoxicity in rats. Sesamin was given orally (5 mg/kg/day, 10 days), and on the 7th day, some of the treated rats were injected intraperitoneally with either saline or CP (5 mg/kg). On the 11th day, rats were sacrificed, and blood and urine samples and kidneys were collected for biochemical estimation of several traditional and novel indices of renal damage in plasma and urine, several oxidative and nitrosative indices in kidneys, and assessment of histopathological renal damage. CP significantly and adversely altered all the physiological, biochemical and histopathological indices of renal function measured. Kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with sesamin. Sesamin treatment did not significantly alter the renal CP concentration. The results suggested that sesamin had ameliorated CP nephrotoxicity in rats by reversing the CP-induced oxidative stress and inflammation. Pending further pharmacological and toxicological studies sesamin may be considered a potentially useful nephroprotective agent.

Topics: Animals; Antineoplastic Agents; Antioxidants; Cisplatin; Dioxoles; Drug Evaluation, Preclinical; Kidney; Kidney Diseases; Lignans; Male; Phytotherapy; Plant Extracts; Rats, Wistar; Sesamum

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway.

Topics: Animals; Biphenyl Compounds; Cell Line; Disease Models, Animal; Fibrosis; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Kidney Diseases; Lignans; Mice; Mitochondrial Dynamics; NF-kappa B; Signal Transduction; Sirtuin 3; Smad Proteins; Transforming Growth Factor beta1

Sesamin is a functional ingredient in sesame (Sesamum indicum) seeds and has many physiological effects. This study investigated whether sesame lignans, sesamin and episesamin (1:1), can suppress age-related disorders of the kidney.. Twenty-month-old mice were divided into three groups, and each group received a regular diet (O-C), diet containing sesame lignans (O-SE), and diet containing sesame lignans and α-tocopherol (VE; O-SE+VE), respectively, for 5 months. Six-month-old young mice (Y-C) were compared to the older mice.. Renal lipofuscin deposition was increased in the O-C group compared to that in the Y-C group and its deposition with aging was significantly decreased in both O-SE and O-SE+VE groups. Plasma blood urea nitrogen levels in the O-C group increased compared to those in the Y-C group; however, those in both O-SE and O-SE+VE groups did not differ from those in the Y-C group. The number of podocytes in the O-C group decreased compared to that in the Y-C group and this effect was attenuated in the O-SE and O-SE+VE groups. The effect was strongest in the O-SE+VE group. Histological examinations showed that glomerular hypertrophy accompanied by mesangial hyperplasia and renal tubular degeneration was less severe in the O-SE and O-SE+VE groups than in the O-C group. Moreover, age-related increases in the mRNA expression of NADPH oxidase- and inflammation-related genes, including p67phox, p40phox, TNFα, and IL-6, in the kidney were suppressed in the O-SE and O-SE+VE groups.. Sesame lignans might be useful to suppress age-related kidney disorders, and these effects could be enhanced with VE.

Topics: Aging; alpha-Tocopherol; Animals; Antioxidants; Diet; Dioxoles; Kidney Diseases; Lignans; Male; Mice; Mice, Inbred C57BL; Sesamum

Renal tubulointerstitial fibrosis (TIF) is commonly the final result of a variety of progressive injuries and leads to end-stage renal disease. There are few therapeutic agents currently available for retarding the development of renal TIF.. The aim of the present study is to evaluate the role of arctigenin (ATG), a lignan component derived from dried burdock (Arctium lappa L.) fruits, in protecting the kidney against injury by unilateral ureteral obstruction (UUO) in rats.. Rats were subjected to UUO and then administered with vehicle, ATG (1 and 3mg/kg/d), or losartan (20mg/kg/d) for 11 consecutive days. The renoprotective effects of ATG were evaluated by histological examination and multiple biochemical assays.. Our results suggest that ATG significantly protected the kidney from injury by reducing tubular dilatation, epithelial atrophy, collagen deposition, and tubulointerstitial compartment expansion. ATG administration dramatically decreased macrophage (CD68-positive cell) infiltration. Meanwhile, ATG down-regulated the mRNA levels of pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) and cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ), in the obstructed kidneys. This was associated with decreased activation of nuclear factor κB (NF-κB). ATG attenuated UUO-induced oxidative stress by increasing the activity of renal manganese superoxide dismutase (SOD2), leading to reduced levels of lipid peroxidation. Furthermore, ATG inhibited the epithelial-mesenchymal transition (EMT) of renal tubules by reducing the abundance of transforming growth factor-β1 (TGF-β1) and its type I receptor, suppressing Smad2/3 phosphorylation and nuclear translocation, and up-regulating Smad7 expression. Notably, the efficacy of ATG in renal protection was comparable or even superior to losartan.. ATG could protect the kidney from UUO-induced injury and fibrogenesis by suppressing inflammation, oxidative stress, and tubular EMT, thus supporting the potential role of ATG in renal fibrosis treatment.

Topics: Animals; Chemokine CCL2; Disease Models, Animal; Epithelial-Mesenchymal Transition; Fibrosis; Furans; Kidney; Kidney Diseases; Lignans; Lipid Peroxidation; Male; NF-kappa B; Oxidative Stress; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Ureteral Obstruction

The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia.

Topics: Actins; Animals; Collagen Type IV; Diet, High-Fat; Dietary Fats; Dioxoles; Dose-Response Relationship, Drug; Dyslipidemias; Gene Expression Regulation; Kidney Diseases; Lignans; Molecular Structure; Oxidative Stress; Rats; Rats, Sprague-Dawley

Magnolin is the major active ingredient of the herb Magnolia fargesii which has anti-inflammatory and antioxidative effects. Oxidative stress and apoptosis are involved in the pathogenesis of contrast-induced nephropathy (CIN). We hypothesize that Magnolin could protect against CIN through antioxidative and antiapoptotic properties.. To test whether Magnolin could attenuate CIN, oxidative stress and apoptosis, in vivo and in vitro, we utilized a rat model of ioversol-induced CIN and a cell model of oxidative stress in which HK2 cells were treated with H2O2. Rats were assigned to 4 groups (n = 6 per group): control group, ioversol group (ioversol-induced CIN), vehicle group (CIN rats pretreated with vehicle), and Magnolin group (CIN rats pretreated with 1 mg/kg Magnolin).. The results showed that magnolin ameliorated the renal tubular necrosis, apoptosis, and the deterioration of renal function (P < 0.05). Furthermore, Magnolin reduced the renal oxidative stress, suppressed caspase-3 activity, and increased Bcl-2 expression in vivo and in vitro.. Magnolin might protect CIN in rats through antioxidation and antiapoptosis.

Topics: Animals; Apoptosis; Contrast Media; Kidney Diseases; Lignans; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Triiodobenzoic Acids

To investigate the protective effects and the underlying mechanism of Eucommia lignans against hypertensive renal injury.. Ten-week-old Wistar Kyoto rats and age matched spontaneously hypertension rats were used in the study. The SHR were randomly divided into 4 groups (n=7 for each group) and received different treatment for 16 weeks, which including saline, Captopril, Epalrestat and Eucommia lignans, respectively. System blood pressures of the rats were monitored once every 4 weeks. N-Acetyl-β-D-glucosaminidase (NAG) activity and the ratio of albumin and urinary creatinine were chosen as the indices of kidney function. Then the structure and renal collagen type III expression of glomerular basement membrane were observed by microscopy and the renal aldose reductase (AR) expression was measured by immunohistochemistry. In vitro, the proliferation of mesangial cells induced by AngII was assayed by MTT, and the mRNA expression of AR was measured by RT-real-time PCR.. The renal function, evaluated by NAG enzyme activity and the ratio of albumin to urinary creatinine, was significantly ameliorated by Eucommia lignans treatment. Meanwhile, Eucommia lignans decreased both the protein (P<0.05) and the mRNA expressed lever of AR (P<0.05). Eucommia lignans also decreased the high expression of collagen type III in SHR (P<0.05) and inhibited the proliferation of renal mesangial cells induced by AngII (P<0.05).. Eucommia lignans have protective effects against hypertensive renal injury, and the protective effects may be partly due to inhibition of aldose reductase.

Topics: Acetylglucosaminidase; Albuminuria; Aldehyde Reductase; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Cell Proliferation; Cells, Cultured; Collagen Type III; Creatinine; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Eucommiaceae; Glomerular Basement Membrane; Hypertension; Immunohistochemistry; Kidney; Kidney Diseases; Lignans; Male; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Time Factors

Schisandrin B (Sch B) is an active ingredient of the fruit of Schisandra chinensis. It has many therapeutic effects arising from its tonic, sedative, antitussive and antiaging activities and is also used in the treatment of viral and chemical hepatitis. The aim of this study was to investigate the protective effects of Sch B on cyclosporine A (CsA)-induced nephrotoxicity in mice and HK-2 cells (a human proximal tubular epithelial cell line). After gavage with Sch B (20 mg/kg) or olive oil (vehicle), mice received CsA (30 mg/kg) by subcutaneous injection once daily for four weeks. Renal function, histopathology, and tissue glutathione (GSH) and malondialdehyde (MDA) levels were evaluated after the last treatment. The effects of Sch B on CsA-induced oxidative damage in HK-2 cells were investigated by measuring cell viability, the release of lactate dehydrogenase (LDH), the level of reactive oxygen species (ROS), and the cellular GSH and ATP concentrations. Cellular apoptosis was assessed by flow cytometry. Treatment with Sch B in CsA-treated mice significantly suppressed the elevation of blood urea nitrogen (BUN) and serum creatinine levels and attenuated the histopathological changes. Additionally, Sch B also decreased renal MDA levels and increased GSH levels in CsA-treated mice. Using an in vitro model, Sch B (2.5, 5 and 10 μM) significantly increased the cell viability and reduced LDH release and apoptosis induced by CsA (10 μM) in HK-2 cells. Furthermore, Sch B increased the intracellular GSH and ATP levels and attenuated CsA-induced ROS generation. In conclusion, Sch B appears to protect against CsA-induced nephrotoxicity by decreasing oxidative stress and cell death.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Blood Urea Nitrogen; Cell Survival; Creatinine; Cyclooctanes; Cyclosporine; Enzyme Inhibitors; Fruit; Glutathione; Humans; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Lignans; Male; Malondialdehyde; Mice; Mice, Inbred Strains; Oxidative Stress; Phytotherapy; Plant Extracts; Polycyclic Compounds; Reactive Oxygen Species; Schisandra

Mercuric chloride (HgCl₂) causes acute oxidant renal failure that affects mainly proximal tubules. Schisandrin B (Sch B), an active lignan from the fruit of Schisandra chinensis, has been successfully used to treat gentamicin nephrotoxicity, but its role against mercury damage is still largely unknown. Here we analysed in vivo and in vitro the efficacy of Sch B supplementation against HgCl₂ nephrotoxicity, focusing on histopathology, stress proteins, oxidative (cytochrome c oxidase) and nitrosactive markers (eNOS, nNOS). Wistar rats were treated with Sch B (10 mg/kg/day p.o.) or vehicle (olive oil) for 9 days, then coadministered with a single HgCl₂ nephrotoxic dose (3.5 mg/kg i.p.) and killed after 24 h. The tubular and mitochondrial damage induced by mercury was limited by Sch B coadministration in vivo. Remarkably, after Sch B and mercury challenge, HSP25, HSP72, GRP75 were reduced in the renal cortex, cytochrome c oxidase increased and eNOS and nNOS were restored in glomeruli. In contrast, NRK-52E proximal tubular cells treated with Sch B 6.25 μM plus HgCl₂ 20 μM did not show any amelioration on viability and oxidative stress in respect to HgCl₂ 20 μM alone. Moreover, after Sch B plus mercury in vitro treatment, HSP72 staining persisted while HSP25 further increased. Thus, in our experimental conditions, Sch B cotreatment afforded better protection against mercury poisoning in vivo than in vitro. This discrepancy might be partly attributable to Sch B influence on glomerular perfusion as corroborated by the recovery of vasoactive markers like macular and endothelial nitric oxide isoforms.

Topics: Animals; Cell Line; Cyclooctanes; Cytochromes c; Dose-Response Relationship, Drug; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Kidney Cortex; Kidney Diseases; Kidney Tubules, Proximal; Lignans; Male; Membrane Proteins; Mercuric Chloride; Mitochondria; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Oxidative Stress; Polycyclic Compounds; Rats; Rats, Wistar

Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In the present study, the effect of long-term Sch B treatment (1-10 mg/kg/d x 15) on gentamicin-induced nephrotoxicity was examined in rats. Sch B treatment protected against gentamicin-induced nephrotoxicity, as evidenced by significant decreases in plasma creatinine and blood urea nitrogen levels. The nephroprotection was associated with the enhancement in renal mitochondrial antioxidant status, as assessed by the level/activity of reduced glutathione, alpha-tocopherol and Mn-superoxide dismutase, as well as the improvement/preservation of mitochondrial functional and structural integrity, as assessed by the extents of ATP generation capacity, malondialdehyde production, Ca2+ loading and cytochrome c release, as well as the sensitivity to Ca2+-induced permeability transition, in control and gentamicin-intoxicated rats. In conclusion, long-term Sch B treatment could enhance renal mitochondrial antioxidant status as well as improve mitochondrial functional and structural integrity, thereby protecting against gentamicin nephrotoxicity.

Topics: Adenosine Triphosphate; Animals; Antibiotics, Antineoplastic; Antioxidants; Ascorbic Acid; Cyclooctanes; Female; Gentamicins; Glutathione; Kidney; Kidney Diseases; Lignans; Mitochondria; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

The antihypertensive effect of sesamin, a lignan from sesame oil, was examined using salt-loaded and unloaded stroke-prone spontaneously hypertensive rats (SHRSP). The animals at 6 weeks of age were separated into a salt-loaded group and an unloaded group. Salt-loaded animals were maintained on 1% NaCl drinking water. Each group was further divided into two groups: normal-diet group and sesamin-diet group. Systolic blood pressure of all animals was monitored once weekly. At the end of the feeding periods, cardiovascular hypertrophy and renal damage were evaluated. In the salt-loaded group, sesamin feeding significantly suppressed the development of hypertension, and efficient suppression was maintained from 9 to 26 weeks (e.g., 215+/-4 vs. 180+/-4 mmHg, at 17 weeks old). The left ventricle plus septum weight-to-body weight ratio was slightly but significantly lowered by sesamin feeding. When the degree of vascular hypertrophy of the aorta and superior mesenteric artery was histochemically evaluated, wall thickness and wall area of these vessels were significantly decreased by the sesamin feeding. Histological renal damage such as thickening of the tunica intima and fibrinoid degeneration of the arterial wall were often observed in the normal-diet group, but this damage was efficiently reduced in the sesamin-fed animals. On the other hand, in the salt-unloaded group, only a slight and nonsignificant suppressive effect of sesamin on the development of hypertension was observed. Although the wall area of the aorta was significantly decreased by the sesamin feeding, other vascular parameters were not ameliorated. The incidence of histological renal damage tended to decrease in sesamin-fed animals, but these alterations were not statistically significant. Thus, sesamin feeding was much more effective as an antihypertensive regimen in salt-loaded SHRSP than in unloaded SHRSP, thereby suggesting that sesamin is more useful as a prophylactic treatment in the malignant status of hypertension and/or hypertension followed by water and salt retention.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Cerebrovascular Disorders; Diet; Dioxoles; Heart Rate; Hypertension; Kidney; Kidney Diseases; Lignans; Male; Myocardium; Rats; Rats, Inbred SHR