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1.
Front Endocrinol (Lausanne) ; 15: 1384953, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38836233

RESUMO

Background: Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation in diabetic kidney disease (DKD) remains inadequately understood. Objective: Therefore, we investigated the changes of NAD+ levels in DKD and the underlying mechanism. Methods: Alternations of NAD+ levels and its biosynthesis enzymes were detected in kidneys from streptozotocin-induced diabetic mouse model by real-time PCR and immunoblot. The distribution of NAD+ de novo synthetic enzymes was explored via immunohistochemical study. NAD+ de novo synthetic metabolite was measured by LC-MS. Human data from NephroSeq were analyzed to verify our findings. Results: The study showed that NAD+ levels were decreased in diabetic kidneys. Both mRNA and protein levels of kynurenine 3-monooxygenase (KMO) in NAD+ de novo synthesis pathway were decreased, while NAD+ synthetic enzymes in salvage pathway and NAD+ consuming enzymes remained unchanged. Further analysis of human data suggested KMO, primarily expressed in the proximal tubules shown by our immunohistochemical staining, was consistently downregulated in human diabetic kidneys. Conclusion: Our study demonstrated KMO of NAD+ de novo synthesis pathway was decreased in diabetic kidney and might be responsible for NAD+ reduction in diabetic kidneys, offering valuable insights into complex regulatory mechanisms of NAD+ in DKD.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , NAD , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , NAD/metabolismo , Humanos , Camundongos , Diabetes Mellitus Experimental/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia
2.
Fa Yi Xue Za Zhi ; 40(2): 186-191, 2024 Apr 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38847035

RESUMO

OBJECTIVES: To explore the postmortem diffusion rule of Aconitum alkaloids and their metabolites in poisoned rabbits, and to provide a reference for identifying the antemortem poisoning or postmortem poisoning of Aconitum alkaloids. METHODS: Twenty-four rabbits were sacrificed by tracheal clamps. After 1 hour, the rabbits were administered with aconitine LD50 in decocting aconite root powder by intragastric administration. Then, they were placed supine and stored at 25 ℃. The biological samples from 3 randomly selected rabbits were collected including heart blood, peripheral blood, urine, heart, liver, spleen, lung and kidney tissues at 0 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h and 96 h after intragastric administration, respectively. Aconitum alkaloids and their metabolites in the biological samples were analyzed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: At 4 h after intragastric administration, Aconitum alkaloids and their metabolites could be detected in heart blood, peripheral blood and major organs, and the contents of them changed dynamically with the preservation time. The contents of Aconitum alkaloids and their metabolites were higher in the spleen, liver and lung, especially in the spleen which was closer to the stomach. The average mass fraction of benzoylmesaconine metabolized in rabbit spleen was the highest at 48 h after intragastric administration. In contrast, the contents of Aconitum alkaloids and their metabolites in kidney were all lower. Aconitum alkaloids and their metabolites were not detected in urine. CONCLUSIONS: Aconitum alkaloids and their metabolites have postmortem diffusion in poisoned rabbits, diffusing from high-content organs (stomach) to other major organs and tissues as well as the heart blood. The main mechanism is the dispersion along the concentration gradient, while urine is not affected by postmortem diffusion, which can be used as the basis for the identification of antemortem and postmortem Aconitum alkaloids poisoning.


Assuntos
Aconitum , Alcaloides , Fígado , Espectrometria de Massas em Tandem , Animais , Coelhos , Aconitum/química , Alcaloides/metabolismo , Alcaloides/urina , Alcaloides/análise , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Fígado/metabolismo , Rim/metabolismo , Pulmão/metabolismo , Aconitina/análogos & derivados , Aconitina/farmacocinética , Aconitina/urina , Aconitina/metabolismo , Aconitina/análise , Raízes de Plantas/química , Distribuição Tecidual , Baço/metabolismo , Mudanças Depois da Morte , Toxicologia Forense/métodos , Miocárdio/metabolismo , Fatores de Tempo , Masculino
3.
Bull Environ Contam Toxicol ; 112(6): 82, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822880

RESUMO

Mercury contamination has been aggravated by emerging environmental issues, such as climate change. Top predators present concerning Hg concentrations once this metal bioaccumulates and biomagnifies. This study evaluated total mercury (THg) concentrations in tissues of 43 franciscanas (Pontoporia blainvillei) from two populations: the Franciscana Management Area (FMA) IIb and FMA IIIa. Animals from FMA IIIa showed mean concentration 5-times and 2.5-times higher in the liver and kidney (4.73 ± 6.84 and 0.52 ± 0.51 µg.g-1, w.w., respectively) than individuals from FMA IIb (0.89 ± 1.04 and 0.22 ± 0.15 µg.g-1, w.w., respectively). This might be due to: (I) individuals sampled from FMA IIIa being larger and older, and/or (II) the area near FMA IIIa presents environmental features leading to higher THg availability. Coastal contamination can affect franciscanas' health and population maintenance at different levels depending on their life history and, therefore, it should be considered to guide specific conservation actions.


Assuntos
Golfinhos , Espécies em Perigo de Extinção , Monitoramento Ambiental , Mercúrio , Poluentes Químicos da Água , Animais , Mercúrio/análise , Mercúrio/metabolismo , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/metabolismo , Oceano Atlântico , Golfinhos/metabolismo , Fígado/metabolismo , Rim/metabolismo
4.
Anal Chim Acta ; 1312: 342758, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38834268

RESUMO

BACKGROUND: The selection of the sample treatment strategy is a crucial step in the metabolomics workflow. Solid phase microextraction (SPME) is a sample processing methodology with great potential for use in untargeted metabolomics of tissue samples. However, its utilization is not as widespread as other standard protocols involving steps of tissue collection, metabolism quenching, homogenization, and extraction of metabolites by solvents. Since SPME allows us to perform all these steps in one action in tissue samples, in addition to other advantages, it is necessary to know whether this methodology produces similar or comparable metabolome and lipidome coverage and performance to classical methods. RESULTS: SPME and homogenization with solid-liquid extraction (Homo-SLE) sample treatment methods were applied to healthy murine kidney tissue, followed by comprehensive metabolomics and lipidomics analyses. In addition, it has been tested whether freezing and storage of the tissue causes alterations in the renal metabolome and lipidome, so the analyses were performed on fresh and frozen tissue samples Lipidomics analysis revealed the exclusive presence of different structural membrane and intracellular lipids in the Homo-SLE group. Conversely, all annotated metabolites were detected in both groups. Notably, the freezing of the sample mainly causes a decrease in the levels of most lipid species and an increase in metabolites such as amino acids, purines, and pyrimidines. These alterations are principally detected in a statistically significant way by SPME methodology. Finally, the samples of both methodologies show a positive correlation in all the analyses. SIGNIFICANCE: These results demonstrate that in SPME processing, as long as the fundamentals of non-exhaustive extraction in a pre-equilibrium kinetic regime, extraction in a tissue localized area, the chemistry of the fiber coating and non-homogenization of the tissue are taken into account, is an excellent method to use in kidney tissue metabolomics; since this methodology presents an easy-to-use, efficient, and less invasive approach that simplifies the different sample processing steps.


Assuntos
Rim , Metabolômica , Microextração em Fase Sólida , Microextração em Fase Sólida/métodos , Animais , Metabolômica/métodos , Rim/metabolismo , Rim/química , Camundongos , Extração Líquido-Líquido/métodos , Metaboloma , Masculino , Camundongos Endogâmicos C57BL
5.
Amino Acids ; 56(1): 38, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844708

RESUMO

Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma D-asparagine and the D/L-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma D-asparagine and the D/L-serine ratio, but dexamethasone treatment did not. Thus, plasma D-asparagine and the D/L-serine ratio can be useful markers for renal function in children.


Assuntos
Asparagina , Biomarcadores , Insuficiência Renal Crônica , Serina , Criança , Animais , Humanos , Asparagina/sangue , Asparagina/metabolismo , Insuficiência Renal Crônica/sangue , Pré-Escolar , Serina/sangue , Camundongos , Masculino , Feminino , Adolescente , Biomarcadores/sangue , Estudos Prospectivos , Dexametasona , Estereoisomerismo , Creatinina/sangue , Rim/metabolismo
6.
J Clin Invest ; 134(11)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38828728

RESUMO

The macula densa (MD) is a distinct cluster of approximately 20 specialized kidney epithelial cells that constitute a key component of the juxtaglomerular apparatus. Unlike other renal tubular epithelial cell populations with functions relating to reclamation or secretion of electrolytes and solutes, the MD acts as a cell sensor, exerting homeostatic actions in response to sodium and chloride changes within the tubular fluid. Electrolyte flux through apical sodium transporters in MD cells triggers release of paracrine mediators, affecting blood pressure and glomerular hemodynamics. In this issue of the JCI, Gyarmati and authors explored a program of MD that resulted in activation of regeneration pathways. Notably, regeneration was triggered by feeding mice a low-salt diet. Furthermore, the MD cells showed neuron-like properties that may contribute to their regulation of glomerular structure and function. These findings suggest that dietary sodium restriction and/or targeting MD signaling might attenuate glomerular injury.


Assuntos
Regeneração , Animais , Regeneração/efeitos dos fármacos , Camundongos , Rim/metabolismo , Humanos , Dieta Hipossódica , Sistema Justaglomerular/metabolismo , Cloreto de Sódio na Dieta , Transdução de Sinais , Glomérulos Renais/metabolismo
7.
Int J Immunopathol Pharmacol ; 38: 3946320241260635, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38831558

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder mainly affecting joints, yet the systemic inflammation can influence other organs and tissues. The objective of this study was to unravel the ameliorative capability of Ondansetron (O) or ß-sitosterol (BS) against inflammatory reactions and oxidative stress that complicates Extra-articular manifestations (EAM) in liver, kidney, lung, and heart of arthritic and arthritic irradiated rats. METHODS: This was accomplished by exposing adjuvant-induced arthritis (AIA) rats to successive weekly fractions of total body γ-irradiation (2 Gray (Gy)/fraction once per week for four weeks, up to a total dose of 8 Gy). Arthritic and/or arthritic irradiated rats were either treated with BS (40 mg/kg b.wt. /day, orally) or O (2 mg/kg) was given ip) or were kept untreated as model groups. RESULTS: Body weight changes, paw circumference, oxidative stress indices, inflammatory response biomarkers, expression of Janus kinase-2 (JAK-2), Signal transducer and activator of transcription 3 (STAT3), high mobility group box1 (HMGB1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), as well as pro- and anti-inflammatory mediators in the target organs, besides histopathological examination of ankle joints and extra-articular tissues. Treatment of arthritic and/or arthritic irradiated rats with BS or O powerfully alleviated changes in body weight gain, paw swelling, oxidative stress, inflammatory reactions, and histopathological degenerative alterations in articular and non-articular tissues. CONCLUSION: The obtained data imply that BS or O improved the articular and EAM by regulating oxidative and inflammatory indices in arthritic and arthritic irradiated rats.


Assuntos
Artrite Experimental , Rim , Fígado , Pulmão , Ondansetron , Estresse Oxidativo , Sitosteroides , Animais , Sitosteroides/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/efeitos da radiação , Artrite Experimental/patologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Rim/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Ratos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Fígado/efeitos da radiação , Masculino , Ondansetron/farmacologia , Proteína HMGB1/metabolismo , Coração/efeitos dos fármacos , Coração/efeitos da radiação , Miocárdio/patologia , Miocárdio/metabolismo , Inflamação/patologia , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Fator de Transcrição STAT3/metabolismo , Ratos Wistar
8.
J Cell Mol Med ; 28(11): e18364, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38837668

RESUMO

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.


Assuntos
Nefropatias Diabéticas , Rim , Metabolismo dos Lipídeos , Humanos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Animais , Rim/metabolismo , Rim/patologia , Macrófagos/metabolismo , Colesterol/metabolismo , Ácidos Graxos/metabolismo , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Oxisteróis/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
9.
BMC Res Notes ; 17(1): 155, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840123

RESUMO

BACKGROUND AND OBJECTIVE: Aspartame (L-aspartyl L-phenylalanine methyl ester) is an artificial sweetener widely used as a sugar substitute. There are concerns regarding the effects of high aspartame doses on the kidney owing to oxidative stress; however, whether the maximum allowed dose of aspartame in humans affects the kidneys remains unknown. Therefore, in this study, we investigated whether the maximum allowed dose of aspartame in humans affects the kidneys. METHODS: In this study, animals were fed a folate-deficient diet to mimic human aspartame metabolism. Eight-week-old ICR mice were divided into control (CTL), 40 mg/kg/day of aspartame-administered (ASP), folate-deficient diet (FD), and 40 mg/kg/day of aspartame-administered with a folate-deficient diet (FD + ASP) groups. Aspartame was administered orally for eight weeks. Thereafter, we evaluated aspartame's effect on kidneys via histological analysis. RESULTS: There were no differences in serum creatinine and blood urea nitrogen levels between the CTL and ASP groups or between the FD and FD + ASP groups. There was no histological change in the kidneys in any group. The expression of superoxide dismutase and 4-hydroxy-2-nonenal in the kidney did not differ between the CTL and ASP groups or the FD and FD + ASP groups. CONCLUSION: Our findings indicate that the allowed doses of aspartame in humans may not affect kidney function or oxidative states.


Assuntos
Aspartame , Rim , Camundongos Endogâmicos ICR , Estresse Oxidativo , Edulcorantes , Animais , Aspartame/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Edulcorantes/farmacologia , Edulcorantes/administração & dosagem , Camundongos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Superóxido Dismutase/metabolismo , Nitrogênio da Ureia Sanguínea
10.
Drug Des Devel Ther ; 18: 1785-1797, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38828020

RESUMO

Objective: Pancreatic surgeries inherently cause ischemia-reperfusion (IR) injury, affecting not only the pancreas but also distant organs. This study was conducted to explore the potential use of dexmedetomidine, a sedative with antiapoptotic, anti-inflammatory, and antioxidant properties, in mitigating the impacts of pancreatic IR on kidney and liver tissues. Methods: A total of 24 rats were randomly divided into four groups: control (C), dexmedetomidine (D), ischemia reperfusion (IR), and dexmedetomidine ischemia reperfusion (D-IR). Pancreatic ischemia was induced in the IR and D-IR groups. Dexmedetomidine was administered intraperitoneally to the D and D-IR groups. Liver and kidney tissue samples were subjected to microscopic examinations after hematoxylin and eosin staining. The levels of thiobarbituric acid reactive substances (TBARS), aryllesterase (AES), catalase (CAT), and glutathione S-transferase (GST) enzyme activity were assessed in liver and kidney tissues. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine were measured. Results: A comparison of the groups revealed that the IR group exhibited significantly elevated TBARS (p < 0.0001), AES (p = 0.004), and CAT enzyme activity (p < 0.0001) levels in the liver and kidney compared to groups C and D. Group D-IR demonstrated notably reduced histopathological damage (p < 0.05) and low TBARS (p < 0.0001), AES (p = 0.004), and CAT enzyme activity (p < 0.0001) in the liver and kidney as well as low AST and ALT activity levels (p < 0.0001) in the serum compared to the IR group. Conclusion: The preemptive administration of dexmedetomidine before pancreatic IR provides significant protection to kidney and liver tissues, as evidenced by the histopathological and biochemical parameters in this study. The findings underscored the potential therapeutic role of dexmedetomidine in mitigating the multiorgan damage associated with pancreatic surgeries.


Assuntos
Dexmedetomidina , Rim , Fígado , Pâncreas , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Dexmedetomidina/farmacologia , Dexmedetomidina/administração & dosagem , Ratos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Ratos Sprague-Dawley
11.
Int J Mol Sci ; 25(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38891834

RESUMO

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent hereditary disorder that affects the kidneys, characterized by the development of an excessive number of fluid-filled cysts of varying sizes in both kidneys. Along with the progression of ADPKD, these enlarged cysts displace normal kidney tissue, often accompanied by interstitial fibrosis and inflammation, and significantly impair renal function, leading to end-stage renal disease. Currently, the precise mechanisms underlying ADPKD remain elusive, and a definitive cure has yet to be discovered. This review delineates the epidemiology, pathological features, and clinical diagnostics of ADPKD or ADPKD-like disease across human populations, as well as companion animals and other domesticated species. A light has been shed on pivotal genes and biological pathways essential for preventing and managing ADPKD, which underscores the importance of cross-species research in addressing this complex condition. Treatment options are currently limited to Tolvaptan, dialysis, or surgical excision of large cysts. However, comparative studies of ADPKD across different species hold promise for unveiling novel insights and therapeutic strategies to combat this disease.


Assuntos
Rim Policístico Autossômico Dominante , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/terapia , Rim Policístico Autossômico Dominante/patologia , Humanos , Animais , Rim/patologia , Rim/metabolismo , Modelos Animais de Doenças
12.
Amino Acids ; 56(1): 42, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38869518

RESUMO

Creatine is a natural nitrogenous organic acid that is integral to energy metabolism and crucial for proper cell functioning. The kidneys are involved in the first step of creatine production. With kidney transplantation being the gold-standard treatment for end-stage kidney disease, kidney transplant recipients (KTR) may be at risk of impaired creatine synthesis. We aimed to compare creatine homeostasis between KTR and controls. Plasma and urine concentrations of arginine, glycine, guanidinoacetate, creatine and creatinine were measured in 553 KTR and 168 healthy controls. Creatine intake was assessed using food frequency questionnaires. Iothalamate-measured GFR data were available in subsets of 157 KTR and 167 controls. KTR and controls had comparable body weight, height and creatine intake (all P > 0.05). However, the total creatine pool was 14% lower in KTR as compared to controls (651 ± 178 vs. 753 ± 239 mmol, P < 0.001). The endogenous creatine synthesis rate was 22% lower in KTR as compared to controls (7.8 ± 3.0 vs. 10.0 ± 4.1 mmol per day, P < 0.001). Despite lower GFR, the plasma guanidinoacetate and creatine concentrations were 21% and 41% lower in KTR as compared to controls (both P < 0.001). Urinary excretion of guanidinoacetate and creatine were 66% and 59% lower in KTR as compared to controls (both P < 0.001). In KTR, but not in controls, a higher measured GFR was associated with a higher endogenous creatine synthesis rate (std. beta: 0.21, 95% CI: 0.08; 0.33; P = 0.002), as well as a higher total creatine pool (std. beta: 0.22, 95% CI: 0.11; 0.33; P < 0.001). These associations were fully mediated (93% and 95%; P < 0.001) by urinary guanidinoacetate excretion which is consistent with production of the creatine precursor guanidinoacetate as rate-limiting factor. Our findings highlight that KTR have a disturbed creatine homeostasis as compared to controls. Given the direct relationship of measured GFR with endogenous creatine synthesis rate and the total creatine pool, creatine supplementation might be beneficial in KTR with low kidney function.Trial registration ID: NCT02811835.Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT02811835 .


Assuntos
Creatina , Homeostase , Transplante de Rim , Rim , Humanos , Creatina/urina , Creatina/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Rim/metabolismo , Glicina/análogos & derivados , Glicina/urina , Glicina/metabolismo , Glicina/sangue , Taxa de Filtração Glomerular , Transplantados , Estudos de Casos e Controles , Creatinina/urina , Creatinina/sangue
13.
Gene ; 926: 148650, 2024 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-38851364

RESUMO

BACKGROUND: Acute kidney injury (AKI) is frequently caused by renal ischemia-reperfusion injury (IRI). Identifying potential renal IRI disease biomarkers would be useful for evaluating AKI severity. OBJECTIVE: We used proteomics and metabolomics to investigate the differences in renal venous blood between ischemic and healthy kidneys in an animal model by identifying differentially expressed proteins (DEPs) and differentially expressed protein metabolites (DEMs). METHODS: Nine pairs of renal venous blood samples were collected before and at 20, 40, and 60 min post ischemia. The ischemia time of Group A, B and C was 20,40 and 60 min. The proteome and metabolome of renal venous blood were evaluated to establish the differences between renal venous blood before and after ischemia. RESULTS: We identified 79 common DEPs in all samples of Group A, 80 in Group B, and 131 in Group C. Further common DEPs among all three groups were Tyrosineprotein kinase, GPR15LG, KAZALD1, ADH1B. We also identified 81, 64, and 83 common DEMs in each group respectively, in which 30 DEMs were further common to all groups. Bioinformatic analysis of the DEPs and DEMs was conducted. CONCLUSION: This study demonstrated that different pathological processes occur during short- and long-term renal IRI. Tyrosine protein kinase, GPR15LG, Kazal-type serine peptidase inhibitor domain 1, and all-trans-retinol dehydrogenase are potential biomarkers of renal IRI.


Assuntos
Injúria Renal Aguda , Biomarcadores , Proteômica , Veias Renais , Traumatismo por Reperfusão , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Animais , Masculino , Proteômica/métodos , Biomarcadores/sangue , Injúria Renal Aguda/sangue , Proteoma , Ratos , Metabolômica/métodos , Rim/metabolismo , Modelos Animais de Doenças , Metaboloma , Ratos Sprague-Dawley , Multiômica
14.
J Nanobiotechnology ; 22(1): 339, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890734

RESUMO

Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-ß1+Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-ß1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/ß-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.


Assuntos
Nefropatias Diabéticas , Vesículas Extracelulares , Fibrose , Células-Tronco Mesenquimais , Análise de Célula Única , Transcriptoma , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Camundongos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Masculino , Camundongos Endogâmicos C57BL , Humanos , Macrófagos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Células Mesangiais/metabolismo , Rim/patologia , Rim/metabolismo
15.
Cardiovasc Diabetol ; 23(1): 199, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867314

RESUMO

BACKGROUND: Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. METHODS: Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. RESULTS: Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. CONCLUSION: This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.


Assuntos
Ciclo do Ácido Cítrico , Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Rim , Fígado , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Metformina/farmacologia , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangue , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Rim/metabolismo , Rim/efeitos dos fármacos , Feminino , Quimioterapia Combinada , Camundongos Endogâmicos C57BL , Metabolômica , Biomarcadores/sangue , Pessoa de Meia-Idade , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Estudos Longitudinais , Camundongos , Idoso , Resultado do Tratamento
16.
PLoS One ; 19(6): e0299389, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38870184

RESUMO

Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis. We evaluated the effects of irisin on renal interstitial fibrosis in UUO mice. The GSE121190, GSE36496, GSE42303, and GSE96101 datasets were downloaded from the Gene Expression Omnibus (GEO) database. In total, 656 differentially expressed genes (DEGs) were identified in normal and UUO mouse renal samples. Periostin and matrix metalloproteinase-2 (MMP-2) were selected to evaluate the effect of irisin on renal fibrosis in UUO mice. In UUO mice, irisin ameliorated renal function, decreased the expression of periostin and MMP-2, and attenuated epithelial-mesenchymal transition and extracellular matrix deposition in renal tissues. In HK-2 cells, irisin treatment markedly attenuated TGF-ß1-induced expression of periostin and MMP-2. Irisin treatment also inhibited TGF-ß1-induced epithelial-mesenchymal transition, extracellular matrix formation, and inflammatory responses. These protective effects of irisin were abolished by the overexpression of periostin and MMP-2. In summary, irisin treatment can improve UUO-induced renal interstitial fibrosis through the TGF-ß1/periostin/MMP-2 signaling pathway, suggesting that irisin may be used for the treatment of renal interstitial fibrosis.


Assuntos
Moléculas de Adesão Celular , Transição Epitelial-Mesenquimal , Fibronectinas , Fibrose , Nefropatias , Metaloproteinase 2 da Matriz , Transdução de Sinais , Fator de Crescimento Transformador beta1 , Obstrução Ureteral , Animais , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/tratamento farmacológico , Fibronectinas/metabolismo , Camundongos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Masculino , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/etiologia , Nefropatias/tratamento farmacológico , Rim/patologia , Rim/metabolismo , Rim/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linhagem Celular , Modelos Animais de Doenças , Periostina
17.
J Am Heart Assoc ; 13(12): e032971, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38842271

RESUMO

BACKGROUND: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. METHODS AND RESULTS: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. CONCLUSIONS: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.


Assuntos
Modelos Animais de Doenças , Fibrose , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Óxido Nítrico Sintase Tipo III , Insuficiência Renal Crônica , Disfunção Ventricular Esquerda , Animais , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Diástole/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Rim/metabolismo , Fosforilação , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Sprague-Dawley , Ratos , Nefrectomia
18.
Sci Rep ; 14(1): 13862, 2024 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-38879688

RESUMO

Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.


Assuntos
Injúria Renal Aguda , Metabolismo Energético , Glutationa , Rim , Fígado , Camundongos Endogâmicos C57BL , Animais , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Fígado/metabolismo , Glutationa/metabolismo , Rim/metabolismo , Masculino , Camundongos , Isquemia/metabolismo , Metabolômica/métodos , Modelos Animais de Doenças , Estresse Oxidativo , Glicólise , Metaboloma
19.
Cell Death Dis ; 15(6): 398, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844470

RESUMO

In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-ß1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV-HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-ß1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-ß1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.


Assuntos
Ferroptose , Fibrose , Proteínas de Homeodomínio , NADPH Oxidase 4 , Insuficiência Renal Crônica , Ferroptose/genética , Animais , NADPH Oxidase 4/metabolismo , NADPH Oxidase 4/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Rim/patologia , Rim/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , Linhagem Celular
20.
Eur J Pharmacol ; 976: 176699, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38825302

RESUMO

Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor 1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe2+ accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe2+ accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.


Assuntos
Atorvastatina , Nefropatias Diabéticas , Ferroptose , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Ferroptose/efeitos dos fármacos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Camundongos Endogâmicos C57BL , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Linhagem Celular , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico
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