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1.
Physiol Rev ; 103(1): 787-854, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36007181

RESUMO

An essential step in renal function entails the formation of an ultrafiltrate that is delivered to the renal tubules for subsequent processing. This process, known as glomerular filtration, is controlled by intrinsic regulatory systems and by paracrine, neuronal, and endocrine signals that converge onto glomerular cells. In addition, the characteristics of glomerular fluid flow, such as the glomerular filtration rate and the glomerular filtration fraction, play an important role in determining blood flow to the rest of the kidney. Consequently, disease processes that initially affect glomeruli are the most likely to lead to end-stage kidney failure. The cells that comprise the glomerular filter, especially podocytes and mesangial cells, express many different types of ion channels that regulate intrinsic aspects of cell function and cellular responses to the local environment, such as changes in glomerular capillary pressure. Dysregulation of glomerular ion channels, such as changes in TRPC6, can lead to devastating glomerular diseases, and a number of channels, including TRPC6, TRPC5, and various ionotropic receptors, are promising targets for drug development. This review discusses glomerular structure and glomerular disease processes. It also describes the types of plasma membrane ion channels that have been identified in glomerular cells, the physiological and pathophysiological contexts in which they operate, and the pathways by which they are regulated and dysregulated. The contributions of these channels to glomerular disease processes, such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, as well as the development of drugs that target these channels are also discussed.


Assuntos
Canalopatias , Glomerulosclerose Segmentar e Focal , Nefropatias , Humanos , Canal de Cátion TRPC6/metabolismo , Canalopatias/metabolismo , Canais de Cátion TRPC/metabolismo , Glomérulos Renais/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Nefropatias/metabolismo
2.
Methods Mol Biol ; 2582: 391-409, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36370365

RESUMO

CCN2 has been shown to be closely involved in the progression of renal fibrosis, indicating the potential of CCN2 inhibition as a therapeutic target. Although the examination of the renal disease phenotypes of adult CCN2 knockout mice has yielded valuable scientific insights, perinatal death has limited studies of CCN2 in vivo. Conditional knockout technology has become widely used to delete genes in the target cell populations or time points using cell-specific Cre recombinase-expressing mice. Therefore, several lines of CCN2-floxed mice have been developed to assess the functional role of CCN2 in adult mice.CCN2 levels are elevated in renal fibrosis and proliferative glomerulonephritis, making them suitable disease models for assessing the effects of CCN2 deletion on the kidney. Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis and transforming growth factor-ß. CCN2 is increased in fibrosis and modulates a number of downstream signaling pathways involved in the fibrogenic properties of TGF-ß. Unilateral ureteral obstruction is one of the most widely used models of renal tubulointerstitial fibrosis. In addition, anti-glomerular basement membrane antibody glomerulonephritis has become the most widely used model for evaluating the effect of increased renal CCN2 expression. Herein, we describe the construction of CCN2-floxed mice and inducible systemic CCN2 conditional knockout mice and methods for the operation of unilateral ureteral obstruction and the induction of anti-glomerular basement membrane antibody glomerulonephritis.


Assuntos
Glomerulonefrite , Nefropatias , Obstrução Ureteral , Camundongos , Animais , Obstrução Ureteral/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Rim/metabolismo , Fibrose , Nefropatias/metabolismo , Camundongos Knockout , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Glomerulonefrite/genética , Glomerulonefrite/metabolismo
3.
Sci Rep ; 12(1): 19160, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357407

RESUMO

Renal fibrosis (RF) is the common pathway for a variety of chronic kidney diseases that progress to end-stage renal disease. Chitosan oligosaccharide (COS) has been identified as possessing many health functions. However, it is not clear whether COS can prevent RF. The purpose of this paper was to explore the action and mechanism of COS in alleviating RF. First, an acute unilateral ureteral obstruction operation (UUO) in male BALB/c mice was performed to induce RF, and COS or fosinopril (positive control drug) were administered for 7 consecutive days. Data from our experiments indicated that COS treatment can significantly alleviate kidney injury and decrease the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) in the UUO mouse model. More importantly, our results show that COS can reduce collagen deposition and decrease the expression of fibrosis proteins, such as collagen IV, fibronectin, collagen I, α-smooth muscle actin (α-SMA) and E-cadherin, ameliorating experimental renal fibrosis in vivo. In addition, we also found that COS suppressed oxidative stress and inflammation in RF model mice. Further studies indicated that the mechanism by which COS alleviates renal fibrosis is closely related to the regulation of the TGF-ß1/Smad pathway. COS has a therapeutic effect on ameliorating renal fibrosis similar to that of the positive control drug fosinopril. Taken together, COS can alleviate renal fibrosis induced by UUO by reducing oxidative stress damage and regulating the TGF-ß1/Smad pathway.


Assuntos
Quitosana , Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Masculino , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Quitosana/metabolismo , Fosinopril/farmacologia , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/patologia , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Oligossacarídeos/metabolismo
4.
Cells ; 11(21)2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36359901

RESUMO

Renal fibrosis is a common pathological feature of various kidney diseases, leading to irreversible renal failure and end-stage renal disease. However, there are still no effective treatments to reverse renal fibrosis. This study aimed to explore the potential mechanism of a targeted drug for fibrosis. Here, unilateral ureteral obstruction (UUO)-treated mice and a TGF-ß1-treated human renal tubular epithelial cell line (HK-2 cells) were used as models of renal fibrosis. Based on the changes of mRNA in UUO kidneys detected by transcriptome sequencing, MK-2206, an Akt inhibitor, was predicted as a potential drug to alleviate renal fibrosis through bioinformatics. We dissolved UUO mice with MK-2206 by gastric gavage and cultured TGF-ß-induced HK-2 cells with MK-2206. Histopathological examinations were performed after MK-2206 intervention, and the degree of renal fibrosis, as well as the expression of Akt/mTOR pathway-related proteins, were evaluated by immunohistochemical staining, immunofluorescence staining, and Western blot. The results showed that MK-2206 significantly improved the pathological structure of the kidney. Furthermore, MK-2206 intervention effectively inhibited UUO- and TGF-ß1-induced epithelial-mesenchymal transition, fibroblast activation, and extracellular matrix deposition. Mechanistically, MK-2206 treatment attenuated the activation of the Akt/mTOR signaling pathway. Taken together, our study revealed for the first time that MK-2206 is a promising drug for the improvement of renal fibrosis.


Assuntos
Nefropatias , Obstrução Ureteral , Camundongos , Humanos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Transdução de Sinais , Obstrução Ureteral/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo
5.
Chem Biol Interact ; 368: 110249, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36347317

RESUMO

Pyroptosis is a pro-inflammatory type of cell death involved in the pathogenesis of multiple kidney diseases, while transcription factor EB (TFEB) is shown to be important for rescuing renal function. Cadmium (Cd) is an omnipresent toxic heavy metal with definite nephrotoxicity, but there is lacking of evidence regarding an interplay between TFEB activity and pyroptosis during Cd exposure. In this study, Cd-exposed NRK-52E cells were used to clarify this issue as an in vitro model of acute kidney injury. First, our results showed that Cd exposure evidently elevated the protein levels involved in pyroptosis, increased lactate dehydrogenase (LDH) release, and disrupted the cell membrane integrity, suggesting the occurrence of pyroptosis in NRK-52E cells. It is also shown that Cd induced a burst of reactive oxygen species (ROS) to mediate pyroptosis. Simultaneously, downregulated TFEB expression with its inhibited nuclear translocation was revealed in Cd-exposed NRK-52E cells. Further investigations have demonstrated that TFEB knockdown promoted Cd-induced ROS production to exacerbate the pyroptosis, while TFEB overexpression inhibited Cd-induced ROS production to alleviate the pyroptosis in NRK-52E cells. In summary, these findings demonstrate that Cd-inhibited TFEB function results in ROS overproduction to promote pyroptosis in NRK-52E cells, which provide new insight into the therapeutic targets for Cd-induced kidney diseases.


Assuntos
Nefropatias , Piroptose , Humanos , Espécies Reativas de Oxigênio/metabolismo , Cádmio/toxicidade , Linhagem Celular , Células Epiteliais/metabolismo , Nefropatias/metabolismo
6.
Cells ; 11(22)2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36429129

RESUMO

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.


Assuntos
Artrogripose , Colestase , Nefropatias , Humanos , Lisossomos/metabolismo , Melanossomas/metabolismo , Doenças Raras/metabolismo , Colestase/metabolismo , Nefropatias/metabolismo
7.
J Vis Exp ; (189)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36408985

RESUMO

Chronic kidney disease (CKD) affects 15% of the U.S. adult population, but the establishment of targeted therapies has been limited by the lack of functional models that can accurately predict human biological responses and nephrotoxicity. Advancements in kidney precision medicine could help overcome these limitations. However, previously established in vitro models of the human kidney glomerulus-the primary site for blood filtration and a key target of many diseases and drug toxicities-typically employ heterogeneous cell populations with limited functional characteristics and unmatched genetic backgrounds. These characteristics significantly limit their application for patient-specific disease modeling and therapeutic discovery. This paper presents a protocol that integrates human induced pluripotent stem (iPS) cell-derived glomerular epithelium (podocytes) and vascular endothelium from a single patient to engineer an isogenic and vascularized microfluidic kidney glomerulus chip. The resulting glomerulus chip is comprised of stem cell-derived endothelial and epithelial cell layers that express lineage-specific markers, produce basement membrane proteins, and form a tissue-tissue interface resembling the kidney's glomerular filtration barrier. The engineered glomerulus chip selectively filters molecules and recapitulates drug-induced kidney injury. The ability to reconstitute the structure and function of the kidney glomerulus using isogenic cell types creates the opportunity to model kidney disease with patient specificity and advance the utility of organs-on-chips for kidney precision medicine and related applications.


Assuntos
Células-Tronco Pluripotentes Induzidas , Nefropatias , Podócitos , Humanos , Glomérulos Renais/metabolismo , Podócitos/metabolismo , Rim , Nefropatias/induzido quimicamente , Nefropatias/metabolismo
8.
BMC Nephrol ; 23(1): 329, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36217118

RESUMO

Two alleles (G1 and G2) of the apolipoprotein 1 gene (APOL1) predispose people of African descent to developing or accelerating the course of certain types of kidney disease. Population studies to determine the frequency of the G1 and G2 alleles are important to inform resource allocation by public health authorities. Traditionally, APOL1 genotyping is carried out in blood samples. However, sample collection, transport, and storage is cumbersome. Here we compared APOL1 genotyping in blood and buccal mucosa cell samples obtained from 23 individuals. Alleles G0 (wild), G1, and G2, as well as genotypes G0/G0, G0/G1, G1/G1, G0/G2, G1/G2, and G2/G2 were detected using both blood and buccal mucosa cells with 100% coincidence. Our data indicate that buccal mucosa cell samples may represent a suitable alternative to blood samples for APOL1 genotyping in the field.


Assuntos
Apolipoproteína L1 , Nefropatias , Alelos , Apolipoproteína L1/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Nefropatias/metabolismo , Mucosa Bucal/metabolismo
9.
Exp Cell Res ; 421(1): 113374, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36206825

RESUMO

Renal fibrosis is a global health concern with limited curative treatment. Canonical transient receptor potential channel 6 (TRPC6), a nonselective cation channel, has been shown to regulate the renal fibrosis in murine models. However, the molecular mechanism is unclear. Fibroblast-myofibroblast transdifferentiation is one of the critical steps in the progression of renal fibrosis. In the present study, we demonstrate that transforming growth factor (TGF)-ß1 exposure significantly increases the TRPC6 expression in renal interstitial fibroblast NRK-49F cells. Pharmacological inhibition of TRPC6 and knockdown of Trpc6 by siRNA alleviate TGF-ß1-increased expression levels of α-smooth muscle actin (α-SMA) and collagen I, two key markers of myofibroblasts. Although direct activation of TRPC6 by 1-oleoyl-2-acetyl-sn-glycerol (OAG) does not affect the expression of α-SMA and collagen I, OAG potentiates TGF-ß1-induced fibroblast-myofibroblast transdifferentiation. Further study demonstrates that TGF-ß1 exposure increases the phosphorylation level of p38 and Yes-associated protein (YAP) translocation into the nuclei. Inhibition of p38 and YAP decreases TGF-ß1-enhanced TRPC6 and α-SMA expression. In conclusion, we demonstrate that TRPC6 is a key regulator of TGF-ß1-induced fibroblast-myofibroblast transdifferentiation and provides the mechanism of how TGF-ß1 exposure regulates TRPC6 expression in NRK-49F fibroblasts.


Assuntos
Transdiferenciação Celular , Nefropatias , Canal de Cátion TRPC6 , Animais , Camundongos , Actinas/metabolismo , Transdiferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/fisiologia , Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Fibrose , Nefropatias/metabolismo , Miofibroblastos/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fatores de Crescimento Transformadores/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/uso terapêutico , Canal de Cátion TRPC6/antagonistas & inibidores , Canal de Cátion TRPC6/genética , Proteínas de Sinalização YAP , Ratos , Modelos Animais de Doenças
10.
Biomolecules ; 12(10)2022 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-36291548

RESUMO

Liver and kidney diseases are the most frequently encountered problems around the globe. Damage to the liver and kidney may occur as a result of exposure to various drugs, chemicals, toxins, and pathogens, leading to severe disease conditions such as cirrhosis, fibrosis, hepatitis, acute kidney injury, and liver and renal failure. In this regard, the use of nanoparticles (NPs) such as silver nanoparticles (AgNPs), gold nanoparticles (AuNPs), and zinc oxide nanoparticles (ZnONPs) has emerged as a rapidly developing field of study in terms of safe delivery of various medications to target organs with minimal side effects. Due to their physical characteristics, NPs have inherent pharmacological effects, and an accidental buildup can have a significant impact on the structure and function of the liver and kidney. By suppressing the expression of the proinflammatory cytokines iNOS and COX-2, NPs are known to possess anti-inflammatory effects. Additionally, NPs have demonstrated their ability to operate as an antioxidant, squelching the generation of ROS caused by substances that cause oxidative stress. Finally, because of their pro-oxidant properties, they are also known to increase the level of ROS, which causes malignant liver and kidney cells to undergo apoptosis. As a result, NPs can be regarded as a double-edged sword whose inherent therapeutic benefits can be refined as we work to comprehend them in terms of their toxicity.


Assuntos
Nefropatias , Nanopartículas Metálicas , Nanopartículas , Óxido de Zinco , Humanos , Ouro/farmacologia , Prata/farmacologia , Nanopartículas Metálicas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Óxido de Zinco/farmacologia , Antioxidantes/farmacologia , Ciclo-Oxigenase 2/metabolismo , Nanopartículas/química , Estresse Oxidativo , Fígado/metabolismo , Citocinas/metabolismo , Nefropatias/metabolismo , Anti-Inflamatórios/farmacologia
11.
Int J Biol Sci ; 18(15): 5897-5912, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36263179

RESUMO

Acidic nuclear phosphoprotein 32 family member e (Anp32e) has been reported to contribute to early mammalian development and cancer metastasis. However, the pathophysiological role of Anp32e in renal interstitial fibrosis (RIF) is poorly understood. Here, we demonstrated that Anp32e was highly expressed in the region of RIF in patients with IgA nephropathy, unilateral ureteral obstruction (UUO) mouse kidneys, and Boston University mouse proximal tubular (BUMPT) cells when treated with TGF-ß1; this upregulation was positively correlated with the total fibrotic area of the kidneys. The overexpression of Anp32e enhanced the TGF-ß1-induced production of fibrosis-related proteins (fibronectin (Fn) and collagen type I (Col-I)) in BUMPT cells whereas the knockdown of Anp32e suppressed the deposition of these fibrosis-related proteins in UUO mice and TGF-ß1-stimulated BUMPT cells. In particular, Anp32e overexpression alone induced the deposition of Fn and Col-I in both mouse kidneys and BUMPT cells without TGF-ß1 stimulation. Furthermore, we revealed that the overexpression of Anp32e induced the expression of TGF-ß1 and p-Smad3 while TGF-ß1 inhibitor SB431542 reversed the Anp32e-induced upregulation of Fn and Col-I in BUMPT cells without TGF-ß1 stimulation. Collectively, our data demonstrate that Anp32e promotes the deposition of fibrosis-related proteins by regulating the TGF-ß1/Smad3 pathway.


Assuntos
Nefropatias , Chaperonas Moleculares , Animais , Camundongos , Linhagem Celular , Colágeno Tipo I/metabolismo , Fibronectinas/metabolismo , Fibrose , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Mamíferos/metabolismo , Chaperonas Moleculares/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo
12.
Oxid Med Cell Longev ; 2022: 2769487, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36267809

RESUMO

Recent studies have focused on nuclear-encoded circular RNAs (circRNAs) in kidney diseases, but little is known about mitochondrial circRNAs. Differentially expressed circRNAs were analyzed by RNA deep sequencing from lupus nephritis (LN) biopsies and normal human kidneys. In LN renal biopsies, the most downregulated circRNA was circMTND5, which is encoded in the mitochondrial genome. We quantitated circMTND5 by qPCR and localized by fluorescence in situ hybridization (FISH). Mitochondrial abnormalities were identified by electron microscopy. The expression of mitochondrial genes was decreased, and the expression of profibrotic genes was increased on qPCR and immunostaining. RNA binding sites for MIR6812 and circMTND5 were predicted. MIR6812 expression was increased by FISH and qPCR. In HK-2 cells and its mitochondrial fraction, the role of circMTND5 sponging MIR6812 was assessed by their colocalization in mitochondria on FISH, RNA immunoprecipitation, and RNA pulldown coupled with luciferase reporter assay. circMTND5 knockdown upregulated MIR6812, decreased mitochondrial functional gene expression, and increased profibrotic gene expression. Overexpression of circMTND5 reversed these effects in hTGF-ß stimulated HK-2 cells. Similar effects were observed in HK-2 cells with overexpression and with knockdown of MIR6812. We conclude that circMTND5 alleviates renal mitochondrial injury and kidney fibrosis by sponging MIR6812 in LN.


Assuntos
Nefropatias , Nefrite Lúpica , MicroRNAs , RNA Circular , Humanos , Fibrose , Hibridização in Situ Fluorescente , Rim/patologia , Nefropatias/genética , Nefropatias/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , RNA Circular/genética
13.
Front Endocrinol (Lausanne) ; 13: 992827, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187097

RESUMO

Background: As a metabolic disease, any abnormality in the aerobic oxidation pathway of glucose may lead to the occurrence of diabetes. This study aimed to investigate the changes in proteins related to aerobic oxidative metabolism in urinary exosomes of diabetic patients and normal controls of different ages, and to further verify their correlation with the pathogenesis of diabetes. Methods: Samples were collected, and proteomic information of urinary exosomes was collected by LC-MS/MS. ELISA was used to further detect the expression of aerobic and oxidative metabolism-related proteins in urinary exosomes of diabetic patients and normal controls of different ages, and to draw receiver operating characteristic (ROC) curve to evaluate its value in diabetes monitoring. Results: A total of 17 proteins involved in aerobic oxidative metabolism of glucose were identified in urinary exosome proteins. Compared with normal control, the expressions of PFKM, GAPDH, ACO2 and MDH2 in diabetic patients were decreased, and the expression of IDH3G was increased. The concentrations of PFKM, GAPDH and ACO2 in urinary exosomes were linearly correlated with the expression of MDH2 (P<0.05). These four proteins vary with age, with the maximum concentration in the 45-59 age group. PFKM, GAPDH, ACO2, and MDH2 in urinary exosomes have certain monitoring value. When used in combination, the AUC was 0.840 (95% CI 0.764-0.915). Conclusions: In diabetic patients, aerobic oxidative metabolism is reduced, and the expression of aerobic oxidative metabolism-related proteins PFKM, GAPDH, ACO2, and MDH2 in urinary exosomes is reduced, which may become potential biomarkers for monitoring changes in diabetes.


Assuntos
Diabetes Mellitus , Exossomos , Nefropatias , Biomarcadores/metabolismo , Cromatografia Líquida , Diabetes Mellitus/metabolismo , Exossomos/metabolismo , Glucose/metabolismo , Humanos , Nefropatias/metabolismo , Estresse Oxidativo , Proteínas/metabolismo , Proteômica , Espectrometria de Massas em Tandem
14.
Oxid Med Cell Longev ; 2022: 2213503, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36193071

RESUMO

Mitochondrial dysfunction is a critical factor contributing to oxidative stress and apoptosis in ischemia-reperfusion (I/R) diseases. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant whose potent anti-I/R injury capacity has been demonstrated in organs such as the heart and the intestine. In the present study, we explored the role of MitoQ in maintaining mitochondrial homeostasis and attenuating oxidative damage in renal I/R injury. We discovered that the decreased renal function and pathological damage caused by renal I/R injury were significantly ameliorated by MitoQ. MitoQ markedly reversed mitochondrial damage after I/R injury and inhibited renal reactive oxygen species production. In vitro, hypoxia/reoxygenation resulted in increased mitochondrial fission and decreased mitochondrial fusion in human renal tubular epithelial cells (HK-2), which were partially prevented by MitoQ. MitoQ treatment inhibited oxidative stress and reduced apoptosis in HK-2 cells by restoring mitochondrial membrane potential, promoting ATP production, and facilitating mitochondrial fusion. Deeply, renal I/R injury led to a decreased expression of sirtuin-3 (Sirt3), which was recovered by MitoQ. Moreover, the inhibition of Sirt3 partially eliminated the protective effect of MitoQ on mitochondria and increased oxidative damage. Overall, our data demonstrate a mitochondrial protective effect of MitoQ, which raises the possibility of MitoQ as a novel therapy for renal I/R.


Assuntos
Nefropatias , Traumatismo por Reperfusão , Sirtuína 3 , Trifosfato de Adenosina/metabolismo , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Homeostase , Humanos , Isquemia/metabolismo , Nefropatias/metabolismo , Mitocôndrias/metabolismo , Compostos Organofosforados/metabolismo , Compostos Organofosforados/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/patologia , Sirtuína 3/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo , Ubiquinona/farmacologia
15.
Clin Sci (Lond) ; 136(20): 1467-1470, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36287192

RESUMO

Podocyte injury due to either drug, toxin, infection, or metabolic abnormality is a great concern as it increases the risk of developing focal segmental glomerulosclerosis (FSGS) and proteinuric kidney diseases. The direct podocyte injury due to doxorubicin is associated with an increase in proinflammatory cytokines and induction of cathepsin L. The increased activity of cathepsin L in turn may degrade the glomerular slit diaphragm resulting in proteinuric kidney injury. The angiotensin-II type 2 receptor (AT2R) has earlier been reported to be associated with the preservation of slit diaphragm proteins and prevention of proteinuria. Recent in vivo findings by Zhang and colleagues further support the anti-proteinuric role of AT2R in preventing podocyte injury via down-regulating cytokines ccl2, and hence, cathepsin L, thereby, limiting the progression of FSGS.


Assuntos
Glomerulosclerose Segmentar e Focal , Nefropatias , Podócitos , Humanos , Glomerulosclerose Segmentar e Focal/prevenção & controle , Glomerulosclerose Segmentar e Focal/metabolismo , Catepsina L/metabolismo , Catepsina L/uso terapêutico , Glomérulos Renais/metabolismo , Podócitos/metabolismo , Proteinúria/metabolismo , Nefropatias/metabolismo , Doxorrubicina , Angiotensinas/metabolismo
16.
Cell Death Dis ; 13(10): 876, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253358

RESUMO

Renal fibrosis is a common pathological feature and outcome of almost all chronic kidney diseases, and it is characterized by metabolic reprogramming toward aerobic glycolysis. Mesenchymal stem cell-derived exosomes (MSC-Exos) have been proposed as a promising therapeutic approach for renal fibrosis. In this study, we investigated the effect of MSC-Exos on glycolysis and the underlying mechanisms. We demonstrated that MSC-Exos significantly ameliorated unilateral ureter obstruction (UUO)-induced renal fibrosis by inhibiting glycolysis in tubular epithelial cells (TECs). miRNA sequencing showed that miR-21a-5p was highly enriched in MSC-Exos. Mechanistically, miR-21a-5p repressed the expression of phosphofructokinase muscle isoform (PFKM), a rate-limiting enzyme of glycolysis, thereby attenuating glycolysis in TECs. Additionally, knockdown of miR-21a-5p abolished the renoprotective effect of MSC-Exos. These findings revealed a novel role for MSC-Exos in the suppression of glycolysis, providing a new insight into the treatment of renal fibrosis.


Assuntos
Exossomos , Nefropatias , Células-Tronco Mesenquimais , MicroRNAs , Fosfofrutoquinase-1 Muscular , Humanos , Exossomos/genética , Exossomos/metabolismo , Fibrose , Glicólise/genética , Nefropatias/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Músculos/metabolismo , Fosfofrutoquinase-1 Muscular/genética , Fosfofrutoquinase-1 Muscular/metabolismo , Isoformas de Proteínas/metabolismo
17.
Oxid Med Cell Longev ; 2022: 7553928, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36285295

RESUMO

The microRNA-214 (miR-214) precursor is formed by the DNM3 gene on human chromosome 1q24.3, which is encoded and transcribed in the nucleus and processed into mature miR-214 in the cytoplasm. Association of miR-214 with the interstitial fibrosis of the kidney has been reported in existing research. Renal interstitial fibrosis is considered necessary during the process of various renal injuries in chronic kidney disease (CKD). One of the important mechanisms is the TGF- (transforming growth factor-) ß1-stimulated epithelial interstitial transformation (EMT). The specific mechanisms of miR-214-3p in renal interstitial fibrosis and whether it participates in EMT are worthy of further investigation. In this paper, we first demonstrated modulation of the downstream PI3K/AKT axis by miR-214-3p through targeting phosphatase and tension protein homologues (PTEN), indicating the miRNA's participation in unilateral ureteral obstruction (UUO) nephropathy and TGF-ß1-induced EMT. We overexpressed or silenced miR-214-3p and PTEN for probing into the correlation of miR-214-3p with PTEN and the downstream PI3K/AKT signalling pathways. According to the results of the study, miR-214-3p overexpression silenced PTEN, activated the PI3K/AKT signalling pathway, and exacerbated EMT induced by TGF-ß1, while miR-214-3p knockdown had the opposite effect. In miR-214-3p knockdown mice, the expression of PTEN was increased, the PI3K/AKT signalling pathway was inhibited, and fibrosis was alleviated. In conclusion, miR-214-3p regulates the EMT of renal tubular cells induced by TGF-ß1 by targeting PTEN and regulating the PI3K/AKT signalling pathway. Furthermore, miR-214-3p knockdown can reduce renal interstitial fibrosis through the PTEN/PI3K/AKT pathway.


Assuntos
Nefropatias , MicroRNAs , Humanos , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fibrose , Nefropatias/genética , Nefropatias/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Crescimento Transformadores/farmacologia , Transição Epitelial-Mesenquimal/genética
18.
Nutrients ; 14(18)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36145066

RESUMO

Megalin is an endocytic receptor abundantly expressed in proximal tubular epithelial cells and other calciotropic extrarenal cells expressing vitamin D metabolizing enzymes, such as bone and parathyroid cells. The receptor functions in the uptake of the vitamin D-binding protein (DBP) complexed to 25 hydroxyvitamin D3 (25(OH)D3), facilitating the intracellular conversion of precursor 25(OH)D3 to the active 1,25 dihydroxyvitamin D3 (1,25(OH)2D3). The significance of renal megalin-mediated reabsorption of 25(OH)D3 and 1,25(OH)2D3 has been well established experimentally, and other studies have demonstrated relevant roles of extrarenal megalin in regulating vitamin D homeostasis in mammary cells, fat, muscle, bone, and mesenchymal stem cells. Parathyroid gland megalin may regulate calcium signaling, suggesting intriguing possibilities for megalin-mediated cross-talk between calcium and vitamin D regulation in the parathyroid; however, parathyroid megalin functionality has not been assessed in the context of vitamin D. Within various models of chronic kidney disease (CKD), megalin expression appears to be downregulated; however, contradictory results have been observed between human and rodent models. This review aims to provide an overview of the current knowledge of megalin function in the context of vitamin D metabolism, with an emphasis on extrarenal megalin, an area that clearly requires further investigation.


Assuntos
Nefropatias , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Calcitriol/metabolismo , Cálcio/metabolismo , Humanos , Rim/metabolismo , Nefropatias/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/metabolismo
19.
Biomed Res Int ; 2022: 5481552, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119923

RESUMO

Chronic kidney disease (CKD) is identified as a widespread chronic progressive disease jeopardizing public health which characterized by gradually loss of renal function. However, there is no efficient therapy to prevail over this disease. Our study was attempting to reveal hirudin's regulation to renal fibrosis as well as the molecular mechanism. We built renal fibrosis models on both cell and animal levels, which were subsequently given with hirudin disposal; then, we performed the transwell assay to estimate the cells' migration and had our detection to relevant proteins with western blot and immunofluorescence. Finally, we commenced both the identification and the determination to the hirudin targeted proteins and its downstream signaling pathways with the methods of network pharmacology. And the results turned out that when it was compared with the model group, the group with hirudin addition came with the suppression in the migration of renal tubular epithelial cells NRK-52E and with a conspicuous decline in the expressions of fibronectin, N-cadherin, vimentin, TGF-ß, and snail. After that, we predicted that there were 17 hirudin target points mainly involving in the PI3K-AKT signaling pathway. Our outcomes of the animal level demonstrated that the conditions of interstitial fibrosis, severe tubular dilatation or atrophy, inflammatory cell infiltration, and massive accumulation of interstitial collagen in the model group were withdrawn after the addition of hirudin. In addition, p-PDGFRß, p-PI3K, and p-AKT protein expressions were significantly reduced, and the PI3K/AKT pathway was downregulated after hirudin treatment in the model group of NRK-52E cells and animals. Therefore, we had our conclusion that hirudin is capable of suppressing the PI3K-AKT signaling pathway as well as the EMT by decreasing PDGFRß phosphorylation.


Assuntos
Nefropatias , Proteínas Proto-Oncogênicas c-akt , Animais , Caderinas/metabolismo , Regulação para Baixo , Transição Epitelial-Mesenquimal , Fibronectinas/metabolismo , Fibrose , Hirudinas/farmacologia , Nefropatias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Vimentina/metabolismo
20.
Eur J Med Res ; 27(1): 176, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088368

RESUMO

Hyperuricemia can induce acute and chronic kidney damage, but the pathological mechanism remains unclear. The potential role of AMP-activated protein kinase (AMPK) α2 in hyperuricemia-induced renal injury was investigated in this study. Acute and chronic hyperuricemic nephropathy was induced by administering intraperitoneal injections of uric acid and oxonic acid to AMPK α2 knockout and wild-type mice. Changes in renal function, histopathology, inflammatory cell infiltration, renal interstitial fibrosis, and urate deposition were analyzed. In both acute and chronic hyperuricemic nephropathy mouse models, knockout of AMPK α2 significantly reduced serum creatinine levels and renal pathological changes. The tubular expression of kidney injury molecule-1 was also reduced in hyperuricemic nephropathy mice deficient in AMPK α2. In addition, knockout of AMPK α2 significantly suppressed the infiltration of renal macrophages and progression of renal interstitial fibrosis in mice with chronic hyperuricemic nephropathy. Knockout of AMPK α2 reduced renal urate crystal deposition, probably through increasing the expression of the uric acid transporter, multidrug resistance protein 4. In summary, AMPK α2 is involved in acute and chronic hyperuricemia-induced kidney injury and may be associated with increased urate crystal deposition in the kidney.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hiperuricemia , Nefropatias , Falência Renal Crônica , Proteínas Quinases Ativadas por AMP/genética , Animais , Modelos Animais de Doenças , Fibrose , Hiperuricemia/induzido quimicamente , Hiperuricemia/genética , Rim/patologia , Nefropatias/genética , Nefropatias/metabolismo , Camundongos , Camundongos Knockout , Ácido Úrico/efeitos adversos , Ácido Úrico/metabolismo
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