The signaling pathway of uromodulin and its role in kidney diseases

Abstract

The uromodulin (UMOD) is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. UMOD acts as a regulatory protein in health and in various conditions. For kidney diseases, its role remains elusive. On one hand, UMOD plays a role in binding and excretion of various potentially injurious products from the tubular fluid. On the other hand, chronic kidney disease is associated with higher serum levels of UMOD. Signaling pathways might be very important in the pathogenesis of kidney diseases. We performed this review to provide a relatively complete signaling pathway flowchart for UMOD to the investigators who were interested in the role of UMOD in the pathogenesis of kidney diseases. Here, we reviewed the signal transduction pathway of UMOD and its role in the pathogenesis of kidney diseases.     

Signaling pathways of prohibitin and its role in diseases

Abstract

Prohibitin (PHB), appearing to be a negative regulator of cell proliferation and to be a tumor suppressor, has been connected to diverse cellular functions including cell cycle control, senescence, apoptosis and the regulation of mitochondrial activities. It is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria and cytoplasmic compartments. However, in different tissues/cells, the expression of PHB was different, such as that it was increased in most of the cancers, but its expression was reduced in kidney diseases. Signaling pathways might be very important in the pathogenesis of diseases. This review was performed to provide a relatively complete signaling pathways flowchart for PHB to the investigators who were interested in the roles of PHB in the pathogenesis of diseases. Here, we review the signal transduction pathways of PHB and its role in the pathogenesis of diseases.     

The signaling pathway of hypoxia inducible factor and its role in renal diseases

Abstract

It is well-documented that hypoxia inducible factor (HIF) is a key mediator of tissue and cellular adaptation to hypoxia. HIF-target genes are also involved in cellular apoptosis and profibrotic mechanisms. The role of HIF in diseases is not consistent. It is a risk factor for tumor progression, whereas it plays a protective role against ischemic hypofusion. For renal diseases, it is not always a risk or protective factor. Many factors are involved in the pathogenesis of renal diseases. It is reported that HIF not only increases hypoxia tolerance, but also regulates a lot of signaling pathways. In the past decades, a number of studies were also conducted to explore the association between HIF and the risk of renal diseases. However, the role of HIF in the development of renal diseases was not entirely clear. In this study, the signal transduction pathways of HIF and its role in the pathogenesis of renal diseases were reviewed.     

Signaling pathway factors expression in renal tissue of apoE-knockout mice

Abstract

Apolipoprotein E (apoE) is regarded as one of the major plasma lipoproteins, and it plays an important role in the transport and metabolism of lipids. apoE can be found in multiple tissues, such as liver, kidney, jejunum, urinary bladder, ileum, colon, brain, adrenal glands, lung, ovary, spleen, pancreas, and testis, etc. As a secreted protein, it plays an important role in the systemic lipoprotein metabolism and vascular wall homeostasis and in the pathogenesis of renal diseases. apoE-knockout (apoE(?/?)) mice is a classic model of atherosclerosis and renal diseases. However, no review summed up the signaling pathway factors expression in renal tissue of apoE-knockout mice. The literatures were searched extensively and this review was performed to review the signaling pathway factors expression in renal tissue of apoE-knockout mice.     

Implications of the PAPP-A-IGFBP-IGF-1 pathway in the pathogenesis and treatment of polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases implicated in the development of end stage renal disease (ESRD). Although FDA has recently approved a drug against ADPKD, there is still a great need for development of alternative management strategies for ADPKD. Understanding the different mechanisms that lead to cystogenesis and cyst expansion in ADPKD is imperative to develop new therapies against ADPKD. Recently, we demonstrated that caloric restriction can prevent the development of cystic disease in animal models of ADPKD and through these studies identified a new role for pregnancy associated plasma protein-A (PAPP-A), a component of the insulin-like growth factors (IGF) pathway, in the pathogenesis of this disease. The PAPP-A-IGF pathway plays an important role in regulation of cell growth, differentiation, and transformation and dysregulation of this pathway has been implicated in many diseases. Several indirect studies support the involvement of IGF-1 in the pathogenesis of ADPKD. However, it was only recently that we described a direct role for a component of this pathway in pathogenesis of ADPKD, opening a new avenue for the therapeutic approaches for this cystic disease. The present literature review will critically discuss the evidence that supports the role of components of IGF pathway in the pathogenesis of ADPKD and discuss the pharmacological implications of PAPP-A-IGF axis in this disease.     

FGF23 ameliorates ischemia-reperfusion induced acute kidney injury via modulation of endothelial progenitor cells: targeting SDF-1/CXCR4 signaling

The levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.Subject terms: Extracellular signalling molecules, DNA methylation, Acute kidney injury, Experimental models of disease     

Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 improves diabetic retinopathy

Diabetes induced a serious of complications including diabetic retinopathy. Our study aimed to investigate the role of Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 in diabetic retinopathy. A mice model of diabetic retinopathy was established, and expression of SDF-1 and CXCR4 in retina was examined by Real-time quantitative PCR (qRT-PCR). Cells of human retinal pigment epithelial cell line ARPE-19 were treated with CXCR4 siRNAs and expression vector, and cell viability was detected by MTT assay. We found that expression of SDF-1 and CXCR4 in retina was significantly downregulated in mice with diabetic retinopathy than in normal healthy mice. High glucose treatment downregulated the expression of SDF-1 and CXCR4 in ARPE-19 cells at both mRNA and protein levels. Transfection with CXCR4 siRNAs decreased, while transfection with CXCR4 expression vector increased cell viability under high glucose treatment. We concluded that SDF-1/CXCR4 pathway improved diabetic retinopathy possibly by increasing cell viability.

Abbreviations: SDF-1: Stromal cell-derived factor 1; CXCL12: C-X-C motif chemokine 12; qRT-PCR: Real-time quantitative PCR     

七氟烷预处理对肺癌细胞凋亡与增殖的影响及机制分析

目的:探讨与分析七氟烷预处理对肺癌细胞凋亡与增殖的影响及机制。方法:采用不同浓度的七氟烷处理肺癌细胞系A549,采用噻唑蓝法检测细胞增殖抑制情况,流式细胞术检测细胞凋亡,Transwell实验检测细胞转移与侵袭,采用免疫印迹法明确七氟烷的具体作用机制。结果:七氟烷处理可导致A549细胞增殖率显著降低,细胞凋亡率显著增加(P0.05),且存在剂量依赖性(P0.05)。同时细胞转移与侵袭指数、基质细胞衍生因子-1 (Stromal cell-derived factor 1,SDF-1)、CXC类趋化因子受体7(CXC chemokine receptor 7,CXCR7)蛋白相对表达量显著降低(P0.05),也存在剂量依赖性(P0.05)。结论:七氟烷预处理能抑制肺癌细胞的SDF-1/CXCR7信号通路,从而促进细胞凋亡,抑制细胞增殖、转移与侵袭。     

The signaling pathway of NADPH oxidase and its role in glomerular diseases

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), a major source of reactive oxygen species, is a critical mediator of redox signaling. It is well-documented that oxidative stress is associated with the development of glomerular diseases (GN). Hence, the Nox was also thought to be involved in the pathogenesis of GN. However, the expression of Nox in various GN was not consistent, the mechanisms by which the activity of the Nox enzymes in regulating renal cells remains unclear. Signaling pathways might be very important in the pathogenesis of GN. We performed this review to provide a relatively complete signaling pathways flowchart for Nox to the investigators who were interested in the role of Nox in the pathogenesis of GN. Here, we reviewed the signal transduction pathway of Nox and its role in the pathogenesis of GN.     

PINK1 protects against cell death induced by mitochondrial depolarization,by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage

Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson''s disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1–Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer.     

Hippo信号通路与心血管发育及疾病调控

心血管疾病已成为中国乃至全球首位死亡原因,探索心血管系统发育及调控异常的原因及相关机制可以为心血管疾病的预防和治疗提供重要的科学依据。Hippo信号通路是新近发现的在调节器官大小、细胞增殖及凋亡、干细胞命运等方面具有重要功能的一条信号通路。Hippo信号通路的不同成分参与心脏血管的发育和心血管细胞增殖、分化等功能调控,影响损伤后修复及再生等过程,该通路调节异常可引起心血管疾病,如心梗、心肌肥大、血管内膜增生、动脉硬化等。本文综述了Hippo信号通路对心血管系统发育和疾病调控的相关研究及最新进展,以期为Hippo通路在心血管疾病的发病机制及临床转化研究提供潜在的理论基础。     

Essential control of mitochondrial morphology and function by chaperone-mediated autophagy through degradation of PARK7

As a selective degradation system, chaperone-mediated autophagy (CMA) is essential for maintaining cellular homeostasis and survival under stress conditions. Increasing evidence points to an important role for the dysfunction of CMA in the pathogenesis of Parkinson disease (PD). However, the mechanisms by which CMA regulates neuronal survival under stress and its role in neurodegenerative diseases are not fully understood. PARK7/DJ-1 is an autosomal recessive familial PD gene. PARK7 plays a critical role in antioxidative response and its dysfunction leads to mitochondrial defects. In the current study, we showed that CMA mediated the lysosome-dependent degradation of PARK7. Importantly, CMA preferentially removed the oxidatively damaged nonfunctional PARK7 protein. Furthermore, CMA protected cells from mitochondrial toxin MPP⁺-induced changes in mitochondrial morphology and function, and increased cell viability. These protective effects were lost under PARK7-deficiency conditions. Conversely, overexpression of PARK7 significantly attenuated the mitochondrial dysfunction and cell death exacerbated by blocking CMA under oxidative stress. Thus, our findings reveal a mechanism by which CMA protects mitochondrial function by degrading nonfunctional PARK7 and maintaining its homeostasis, and dysregulation of this pathway may contribute to the neuronal stress and death in PD pathogenesis.     

Regulation of plasticity and biological features of endothelial progenitor cells by MSC-derived SDF-1

Bone marrow (BM) is a source of mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs). MSCs provide a specific niche in the BM and biological features of EPCs may be changed with this niche. Stromal cell-derived factor 1 (SDF-1) secreted from primary BM-MSCs and biological features of this niche on EPC development are still yet to be understood. The aim of this study was to evaluate the role of SDF-1 produced by MSCs on EPC development. We applied the CRISPR/Cas9 system for the knock-out of the SDF-1 gene in BM-derived MSCs. BM-derived EPCs were then cocultured with MSCs^SDF-1−/− or MSCs^SDF-1+/+ to identify the role of MSC-derived SDF-1α on proliferation, migration and angiogenic activity of EPCs. Next, pre-expanded EPCs were harvested and co-transplanted with MSCs^SDF-1−/− or MSCs^SDF-1+/+ into sublethally irradiated mice to analyze the potency of these cells for marrow reconstitution. Our results revealed that proliferation, colony formation, migration and angiogenic activity of EPCs was significantly increased after coculture with MSCs^SDF-1+/+. We also found that co-transplantation of EPCs with MSCs^SDF-1+/+, in contrast to MSCs^SDF-1−/−, into irradiated mice resulted in marrow repopulation and hematologic recovery, leading to improved survival of transplanted mice. In conclusions, MSC-derived SDF-1 niche plays an important role in the development of EPCs and this niche is essential for bone marrow repopulation by these cells and can enhance the efficiency of EPC therapy for ischemic diseases.     

Role of ferroptosis in cisplatin-induced acute nephrotoxicity in mice

BackgroundCisplatin is widely used as an antitumor drug for the treatment of solid tumors. However, its use has been limited owing to nephrotoxicity, a major side effect. The mechanism of cisplatin-induced nephrotoxicity (CIN) has long been investigated in order to develop preventive/therapeutic drugs. Ferroptosis is a newly identified form of non-apoptotic regulated cell death induced by iron-mediated lipid peroxidation and is involved in the pathophysiology of various diseases. In this study, we examined the role of ferroptosis in CIN.MethodsWe evaluated the role of ferroptosis in CIN by in vivo experiments in a mouse model.ResultsCisplatin increased the protein expressions of transferrin receptor-1 and ferritin, and iron content in the kidney of mice. In addition, treatment with cisplatin augmented renal ferrous iron and hydroxyl radical levels with co-localization. Mice administered cisplatin demonstrated kidney injury, with renal dysfunction and increased inflammatory cytokine expression; these changes were ameliorated by Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis. The expression of the ferroptosis markers, COX2 and 4-hydroxynonenal (4-HNE), increased with cisplatin administration, and decreased with the administration of Fer-1. By contrast, cisplatin-induced apoptosis and necroptosis were inhibited by treatment with Fer-1. Moreover, deferoxamine, an iron chelator, also inhibited CIN, with a decrease in the expression of COX-2 and 4-HNE.ConclusionFerroptosis is involved in the pathogenesis of CIN and might be used as a new preventive target for CIN.     

Role of miR-107 and its signaling pathways in diseases

Abstract

MicroRNAs exert their biologic effects by targeting specific mRNAs for degradation or translational inhibition. MicroRNA-mediated regulation is complex, potentially affecting expression of the host gene, related enzymes within the same pathway or apparently distinct targets. miR-107 is found to be implicated in the pathogenesis of some diseases. This review was performed to sum up the role of miR-107 and its signaling pathways in renal diseases.     

Renal cystic disease in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is associated with TSC1 or TSC2 gene mutations resulting in hyperactivation of the mTORC1 pathway. This mTORC1 activation is associated with abnormal tissue development and proliferation such that in the kidney there are both solid tumors and cystic lesions. This review summarizes recent advances in tuberous sclerosis complex nephrology and focuses on the genetics and cell biology of tuberous sclerosis complex renal disease, highlighting a role of extracellular vesicles and the innate immune system in disease pathogenesis.     

The role of A-kinase interacting protein 1 in regulating progression and stemness as well as indicating the prognosis in glioblastoma

BackgroundA-kinase interacting protein 1 (AKIP1) is recently implicated in the pathogenesis of several solid tumors, while its role in glioblastoma multiforme (GBM) is largely unknown. Therefore, the current study aimed to investigate the effect of AKIP1 on GBM cell malignant behaviors, stemness, and its underlying molecular mechanisms.MethodsU-87 MG and A172 cells were transfected with control or AKIP1 overexpression plasmid; control or AKIP1 siRNA plasmid. Then cell proliferation, apoptosis, invasion, CD133⁺ cell proportion, and sphere formation assays were performed. Furthermore, RNA-Seq was performed in U-87 MG cells. Besides, AKIP1 expression was detected in 25 GBM and 25 low-grade glioma (LGG) tumor samples.ResultsAKIP1 was increased in several GBM cell lines compared to the control cell line. After transfections, it was found that AKIP1 overexpression increased cell invasion, CD133⁺ cell proportion, and sphere formation ability while less affecting cell proliferation or cell apoptosis in U-87 MG and A172 cells. Moreover, AKIP1 siRNA achieved the opposite effect in these cells, except that it inhibited cell proliferation but induced cell apoptosis to some extent. Subsequent RNA-Seq assay showed several critical carcinogenetic pathways, such as PI3K/AKT, Notch, EGFR tyrosine kinase inhibitor resistance, Ras, ErbB, mTOR pathways, etc. were potentially related to the function of AKIP1 in U-87 MG cells. Clinically, AKIP1 expression was higher in GBM tissues than in LGG tissues, which was also correlated with the poor prognosis of GBM to some degree.ConclusionsAKIP1 regulates the malignant behaviors and stemness of GBM via regulating multiple carcinogenetic pathways.