Klotho Deficiency Aggravates Tacrolimus-Induced Renal Injury via the Phosphatidylinositol 3-Kinase-Akt-Forkhead Box Protein O Pathway

2016 ◽  
Vol 43 (5) ◽  
pp. 357-365 ◽  
Author(s):  
Jian Jin ◽  
Long Jin ◽  
Sun Woo Lim ◽  
Chul Woo Yang
Keyword(s):  
Oxidative Stress ◽  
Experimental Model ◽  
Renal Injury ◽  
Manganese Superoxide Dismutase ◽  
Target Genes ◽  
Dependent Manner ◽  
Protective Effects ◽  
Phosphatidylinositol 3 Kinase ◽  
Forkhead Box ◽  
Phosphatidylinositol 3

Background: Klotho is highly expressed in the kidney, is present in the circulation and urine, and has protective effects against various renal injuries. We examined whether reduced Klotho expression affects tacrolimus (Tac)-induced renal injury in an experimental model of chronic Tac nephropathy. Methods: First, we evaluated the association between the Tac dose and Klotho expression by giving different doses of Tac (0.25, 0.5, and 1 mg/kg) to wild-type (WT) mice for 4 weeks. Second, we compared Klotho levels, renal function, fibrosis, and apoptosis between WT mice and Klotho heterozygous (HT) mice in an experimental model of chronic Tac nephropathy. Third, we examined whether the oxidative stress and signaling pathway are involved in the protection by Klotho against Tac-induced renal injury. Results: Klotho levels in renal tissue and urine were reduced in a dose-dependent manner in Tac-treated WT mice. Tac-treated HT mice showed lower levels of Klotho in the renal cortex and urine, and higher serum creatinine level, fibrosis, and apoptosis compared with WT mice. Treatment of Tac to WT mice increased markers of oxidative stress such as phosphatidylinositol 3-kinase (PI3K)-Akt and Forkhead box protein O (FoxO) 3a phosphorylation but decreased FoxO1 dephosphorylation. These effects were greater in HT mice. HT mice exhibited a much lower level of manganese superoxide dismutase level and higher level of Bim, target genes of FoxOs, compared with the levels in WT mice. Conclusion: Reduced Klotho expression aggravates Tac-induced renal injury via the PI3K-Akt-FoxO pathway.

scholarly journals Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus

2018 ◽  
Vol 314 (3) ◽  
pp. F462-F470 ◽  
Author(s):  
Yoshifumi Kurosaki ◽  
Akemi Imoto ◽  
Fumitaka Kawakami ◽  
Masanori Yokoba ◽  
Tsuneo Takenaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Hydrogen Peroxide ◽  
High Glucose ◽  
Renal Cortex ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphorylated Akt ◽  
Stress Dependent ◽  
Phosphatidylinositol 3

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

scholarly journals Tanshinol Attenuates the Deleterious Effects of Oxidative Stress on Osteoblastic Differentiation via Wnt/FoxO3a Signaling

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Yajun Yang ◽  
Yanjie Su ◽  
Dongtao Wang ◽  
Yahui Chen ◽  
Tie Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Osteoblastic Differentiation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Cycle Arrest ◽  
Deleterious Consequence ◽  
Wnt Signal

There is now increasing evidence which suggests a pivotal role for oxidative stress in the development and progression of osteoporosis. We confirm herein the protective effects of natural antioxidant Tanshinol against oxidative stress in osteoblastic differentiation and the underlying mechanism. Our results show that hydrogen peroxide (H2O2) leads to accumulation of reactive oxygen species (ROS), decrease in cell viability, cell cycle arrest and apoptosis in a caspase-3-dependent manner, and inhibition of osteoblastic differentiation. Tanshinol reverses these deleterious consequence triggered by oxidative stress. Moreover, under the condition of oxidative stress, Tanshinol suppresses the activation of FoxO3a transcription factor and expressions of its target genesGadd45aandcatalase (CAT)and simultaneously counteracts the inhibition of Wnt signalling and expressions of target genesAxin2,alkaline phosphatase (ALP), andOsteoprotegerin (OPG). The findings are further consolidated using FoxO3a siRNA interference and overexpression of Tcf4. The results illustrate that Tanshinol attenuates oxidative stress via down-regulation of FoxO3a signaling, and rescues the decrease of osteoblastic differentiation through upregulation of Wnt signal under oxidative stress. The present findings suggest that the beneficial effects of Tanshinol may be adopted as a novel therapeutic approach in recently recognized conditions of niche targeting osteoporosis.

scholarly journals Inhalation of Hydrogen of Different Concentrations Ameliorates Spinal Cord Injury in Mice by Protecting Spinal Cord Neurons from Apoptosis, Oxidative Injury and Mitochondrial Structure Damages

2018 ◽  
Vol 47 (1) ◽  
pp. 176-190 ◽  
Author(s):  
Xiao Chen ◽  
Jin Cui ◽  
Xiao Zhai ◽  
Jun Zhang ◽  
Zhengrong Gu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Target Genes ◽  
Ros Generation ◽  
Hydrogen Treatment ◽  
Dependent Manner ◽  
Protective Effects ◽  
Spinal Cord Neurons ◽  
Cord Injury

Background/Aims: Hydrogen selectively neutralizes reactive oxygen species (ROS) and ameliorates various ROS-induced injuries. Spinal cord injury (SCI) is a serious injury to the central nervous system, and secondary SCI is closely related to excessive ROS generation. We hypothesized that hydrogen inhalation ameliorates SCI, and the mechanism of action may be related to the protective effects of hydrogen against oxidative stress, apoptosis, and mitochondrial damage. Methods: Mechanically injured spinal cord neurons were incubated with different concentrations of hydrogen in vitro. Immunofluorescence staining and transmission electron microscopy were used to confirm the protective effects of hydrogen. ROS and related proteins were detected with dihydroethidium fluorescence staining, enzyme-linked immunosorbent assays, and western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, flow cytometry, and western blotting were used to detect neuronal apoptosis. ATP concentrations, Janus Green B staining, and mitochondrial permeability transition pore (mPTP) status were assessed to investigate mitochondrial damage. RNA sequencing was performed to screen potential target genes of hydrogen application. Hydrogen was administered to mice after spinal cord contusion injury was established for 42 days. The Basso Mouse Scale (BMS) and footprint analyses were used to assess locomotor functions, and immunofluorescence staining of the injured spinal cord segments was performed to detect oxidative stress status. Results: Spinal cord neurons were preserved by hydrogen administration after mechanical injury in a dose-dependent manner. ROS generation, oxidative stress injury-related markers, and the number of apoptotic neurons were significantly reduced after hydrogen treatment. The ATP production and mPTP function in injured neurons were preserved by hydrogen incubation. The expression levels of Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were inhibited by hydrogen treatment. BMS scores and the footprint assessment of mice with SCI were improved by hydrogen inhalation. Conclusions: Hydrogen inhalation (75%) ameliorated SCI in vivo and attenuated neuronal mechanical injuries in vitro, and its protective effect on spinal cord neurons was exerted in a dose-dependent manner. The underlying mechanisms included reducing ROS generation and oxidative stress, inhibiting neuronal apoptosis, and restoring mitochondrial construction and function. Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were identified as potential target genes of hydrogen treatment.

scholarly journals Role of phosphatidylinositol 3-kinase in oxidative stress-induced disruption of tight junctions. Vol. 278 (2003) 49239-49245

2004 ◽  
Vol 279 (7) ◽  
pp. 6204
Author(s):  
Parimal Sheth ◽  
Shyamali Basuroy ◽  
Chunying Li ◽  
Anjaparavanda P. Naren ◽  
Radhakrishna K. Rao
Keyword(s):  
Oxidative Stress ◽  
Tight Junctions ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 572
Author(s):  
Jung-Yeon Kim ◽  
Jungmin Jo ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Injury ◽  
Manganese Superoxide Dismutase ◽  
Immune Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Pleiotropic Effects ◽  
Induced Apoptosis ◽  
Vascular Adhesion

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

scholarly journals Both Src-Dependent and -Independent Mechanisms Mediate Phosphatidylinositol 3-Kinase Regulation of Colony-Stimulating Factor 1-Activated Mitogen-Activated Protein Kinases in Myeloid Progenitors

2000 ◽  
Vol 20 (18) ◽  
pp. 6779-6798 ◽  
Author(s):  
Angel W.-M. Lee ◽  
David J. States
Keyword(s):  
Kinase Inhibitors ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Stimulating Factor ◽  
In Cells ◽  
Phosphatidylinositol 3 ◽  
Myeloid Progenitors

ABSTRACT Colony-stimulating factor 1 (CSF-1) supports the proliferation, survival, and differentiation of bone marrow-derived cells of the monocytic lineage. In the myeloid progenitor 32D cell line expressing CSF-1 receptor (CSF-1R), CSF-1 activation of the extracellular signal-regulated kinase (ERK) pathway is both Ras and phosphatidylinositol 3-kinase (PI3-kinase) dependent. PI3-kinase inhibition did not influence events leading to Ras activation. Using the activity of the PI3-kinase effector, Akt, as readout, studies with dominant-negative and oncogenic Ras failed to place PI3-kinase downstream of Ras. Thus, PI3-kinase appears to act in parallel to Ras. PI3-kinase inhibitors enhanced CSF-1-stimulated A-Raf and c-Raf-1 activities, and dominant-negative A-Raf but not dominant-negative c-Raf-1 reduced CSF-1-provoked ERK activation, suggesting that A-Raf mediates a part of the stimulatory signal from Ras to MEK/ERK, acting in parallel to PI3-kinase. Unexpectedly, a CSF-1R lacking the PI3-kinase binding site (ΔKI) remained capable of activating MEK/ERK in a PI3-kinase-dependent manner. To determine if Src family kinases (SFKs) are involved, we demonstrated that CSF-1 activated Fyn and Lyn in cells expressing wild-type (WT) or ΔKI receptors. Moreover, CSF-1-induced Akt activity in cells expressing ΔKI is SFK dependent since Akt activation was prevented by pharmacological or genetic inhibition of SFK activity. The docking protein Gab2 may link SFK to PI3-kinase. CSF-1 induced Gab2 tyrosyl phosphorylation and association with PI3-kinase in cells expressing WT or ΔKI receptors. However, only in ΔKI cells are these events prevented by PP1. Thus in myeloid progenitors, CSF-1 can activate the PI3-kinase/Akt pathway by at least two mechanisms, one involving direct receptor binding and one involving SFKs.

scholarly journals Wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase, induces accumulation of DNA double-strand breaks

2020 ◽  
Vol 61 (2) ◽  
pp. 171-176 ◽  
Author(s):  
Makoto Ihara ◽  
Kazuko Shichijo ◽  
Satoshi Takeshita ◽  
Takashi Kudo
Keyword(s):  
Dna Damage ◽  
Specific Inhibitor ◽  
Double Strand Breaks ◽  
Dependent Manner ◽  
Dna Double Strand Breaks ◽  
Phosphatidylinositol 3 Kinase ◽  
Strand Breaks ◽  
Γ Ray ◽  
Scid Cells ◽  
Phosphatidylinositol 3

Abstract Wortmannin, a fungal metabolite, is a specific inhibitor of the phosphatidylinositol 3-kinase (PI3K) family, which includes double-stranded DNA dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated kinase (ATM). We investigated the effects of wortmannin on DNA damage in DNA-PK-deficient cells obtained from severe combined immunodeficient mice (SCID cells). Survival of wortmannin-treated cells decreased in a concentration-dependent manner. After treatment with 50 μM wortmannin, survival decreased to 60% of that of untreated cells. We observed that treatment with 20 and 50 μM wortmannin induced DNA damage equivalent to that by 0.37 and 0.69 Gy, respectively, of γ-ray radiation. The accumulation of DNA double-strand breaks (DSBs) in wortmannin-treated SCID cells was assessed using pulsed-field gel electrophoresis. The maximal accumulation was observed 4 h after treatment. Moreover, the presence of DSBs was confirmed by the ability of nuclear extracts from γ-ray-irradiated SCID cells to produce in vitro phosphorylation of histone H2AX. These results suggest that wortmannin induces cellular toxicity by accumulation of spontaneous DSBs through inhibition of ATM.

scholarly journals Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 Mediates Antiestrogen Resistance in Human Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 43 ◽  
Author(s):  
Nicholas Pulliam ◽  
Jessica Tang ◽  
Weini Wang ◽  
Fang Fang ◽  
Riddhi Sood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Dependent Manner ◽  
Tamoxifen Resistant

Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifen with a PARP1 inhibitor (PARPi) would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylation with tamoxifen resistance and indicate a novel mechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer.

scholarly journals Hydrogen Gas Alleviates Chronic Intermittent Hypoxia-Induced Renal Injury through Reducing Iron Overload

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1184 ◽  
Author(s):  
Peng Guan ◽  
Zhi-Min Sun ◽  
Li-Fei Luo ◽  
Ya-Shuo Zhao ◽  
Sheng-Chang Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Renal Injury ◽  
Intermittent Hypoxia ◽  
Hydrogen Gas ◽  
Chronic Intermittent Hypoxia ◽  
Protective Effects ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
And Oxidative Stress

Iron-induced oxidative stress has been found to be a central player in the pathogenesis of kidney injury. Recent studies have indicated H2 can be used as a novel antioxidant to protect cells. The present study was designed to investigate the protective effects of H2 against chronic intermittent hypoxia (CIH)-induced renal injury and its correlation mechanism involved in iron metabolism. We found that CIH-induced renal iron overloaded along with increased apoptosis and oxidative stress. Iron accumulates mainly occurred in the proximal tubule epithelial cells of rats as showed by Perl’s stain. Moreover, we found that CIH could promote renal transferrin receptor and divalent metal transporter-1 expression, inhibit ceruloplasmin expression. Renal injury, apoptosis and oxidative stress induced by CIH were strikingly attenuated in H2 treated rats. In conclusion, hydrogen may attenuate CIH-induced renal injury at least partially via inhibiting renal iron overload.

Sign in / Sign up

Export Citation Format

Share Document