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1.
Kidney Int ; 95(6): 1359-1372, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30905471

RESUMO

In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GECs) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel(ENaC), which is expressed by GEC, upon binding to the channel's α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E2 and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Glomerulonefrite/tratamento farmacológico , Glomérulos Renais/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Proteinúria/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Dinoprostona/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Glomerulonefrite/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Injeções Intraperitoneais , Glomérulos Renais/citologia , Glomérulos Renais/patologia , Camundongos , Óxido Nítrico/metabolismo , Técnicas de Patch-Clamp , Cultura Primária de Células , Proteinúria/sangue , Proteinúria/imunologia , Proteinúria/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
2.
Kidney Int ; 94(2): 280-291, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29731111

RESUMO

To investigate the role of protein kinase C-α (PKC-α) in glomerulonephritis, the capacity of PKC-α inhibition to reverse the course of established nephrotoxic nephritis (NTN) was evaluated. Nephritis was induced by a single injection of nephrotoxic serum and after its onset, a PKC-α inhibitor was administered either systemically or by targeted glomerular delivery. By day seven, all mice with NTN had severe nephritis, whereas mice that received PKC-α inhibitors in either form had minimal evidence of disease. To further understand the underlying mechanism, label-free shotgun proteomic analysis of the kidney cortexes were performed, using quantitative mass spectrometry. Ingenuity pathway analysis revealed 157 differentially expressed proteins and mitochondrial dysfunction as the most modulated pathway. Functional protein groups most affected by NTN were mitochondrial proteins associated with respiratory processes. These proteins were down-regulated in the mice with NTN, while their expression was restored with PKC-α inhibition. This suggests a role for proteins that regulate oxidative phosphorylation in recovery. In cultured glomerular endothelial cells, nephrotoxic serum caused a decrease in mitochondrial respiration and membrane potential, mitochondrial morphologic changes and an increase in glycolytic lactic acid production; all normalized by PKC-α inhibition. Thus, PKC-α has a critical role in NTN progression, and the results implicate mitochondrial processes through restoring oxidative phosphorylation, as an essential mechanism underlying recovery. Importantly, our study provides additional support for targeted therapy to glomeruli to reverse the course of progressive disease.


Assuntos
Glomerulonefrite/tratamento farmacológico , Proteína Quinase C-alfa/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Anticorpos Monoclonais/imunologia , Autoantígenos/imunologia , Colágeno Tipo IV/imunologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Hibridomas , Soros Imunes/administração & dosagem , Soros Imunes/imunologia , Fragmentos de Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Proteína Quinase C-alfa/imunologia , Proteína Quinase C-alfa/metabolismo , Inibidores de Proteínas Quinases/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
3.
J Immunol ; 194(12): 5713-24, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25980011

RESUMO

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.


Assuntos
Aminoácidos/metabolismo , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/metabolismo , Autoanticorpos/imunologia , Autofagia/imunologia , Animais , Doença Antimembrana Basal Glomerular/genética , Doença Antimembrana Basal Glomerular/patologia , Citocinas/biossíntese , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Camundongos Knockout , Podócitos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Estresse Fisiológico
4.
Am J Physiol Renal Physiol ; 309(8): F680-4, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26290372

RESUMO

Current therapies to limit kidney disease progression lack specificity and often have systemic toxicity. To approach this problem, we postulated that a human monoclonal antibody (F1.1), directed against the noncollagenous-1 domain (NC1) of α3(IV) collagen that localizes in glomeruli, could serve as a vehicle for targeted drug delivery. Given enhanced exposure of the NC1 domain of α3(IV) during glomerular diseases, with limited epitope expression in other organs, α3(IV)NC1 provides an ideal target for delivery of disease-modifying agents. As a potential disease-modifying agent, we initially took advantage of recent observations that PGE2 promoted recovery after established injury during the course of nephrotoxic nephritis. To address the general applicability of the approach, the efficacy of glomerular delivery of dexamethasone was also examined. To achieve glomerular targeted therapy, PGE2 and dexamethasone were coupled to F1.1. After confirmation of the composition and activity of the conjugates, both glomerular localization and the capacity of the conjugates to modify disease were evaluated. After injection into mice with established nephritis, resolution of disease was enhanced with both agents, with normalization of histology and improved blood urea nitrogen levels in conjugate-treated mice compared with untreated mice. The results provide a novel means of targeting glomeruli during nephritis, irrespective of cause, by providing efficient drug delivery, with the potential of limiting systemic effects.


Assuntos
Doença Antimembrana Basal Glomerular/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Autoantígenos/imunologia , Colágeno Tipo IV/imunologia , Dexametasona/análogos & derivados , Dinoprostona/análogos & derivados , Imunoconjugados/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Nefrite/tratamento farmacológico , Animais , Doença Antimembrana Basal Glomerular/induzido quimicamente , Anti-Inflamatórios/uso terapêutico , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Dexametasona/uso terapêutico , Dinoprostona/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Hepatócitos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/imunologia , Podócitos/efeitos dos fármacos , Ovinos
5.
Am J Physiol Renal Physiol ; 304(5): F463-70, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23283994

RESUMO

We postulated that prostaglandin E2 (PGE2), which exhibits regulatory functions to control immune-mediated inflammation, fibrosis, oxidative stress, and tissue/cellular regeneration, has the potential to improve the course of nephritis. Therefore, the therapeutic potential of prostanoid on established nephritis in mice was evaluated focusing on its role on renal cellular recovery, with emphasis on its cytoprotecting and growth-promoting effects. Acute nephritis was induced in mice by single injection of nephrotoxic serum (NTS), followed by PGE2 administration with severity of nephritis evaluated over time. Mice injected with PGE2 recovered promptly with normalization of blood urea nitrogen and urine protein levels and histology. Recovery was observed with dosing of prostanoid at day 1, as well as day 4. With the use of selective EP1-4 receptor agonists, EP3 receptor has been identified as important in mediating beneficial effects of PGE2 in our system. PGE2 normalized glomerular cell losses during nephrotoxic serum-induced nephritis, restored synaptopodin distribution and F-actin filaments arrangement in glomeruli. In cell culture, PGE2 reduced nephrotoxim serum (NTS)-induced apoptosis of glomerular cells and promoted cell reproliferation after NTS-mediated injury. In conclusion, PGE2 treatment promotes resolution of glomerular inflammation. Consistent with this observation, the regenerative and cytoprotective effects of prostanoid on glomerular cells in culture were observed, suggesting that PGE2 may be beneficial in the treatment of glomerulonephritis.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Nefrite/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Dinoprostona/farmacologia , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Camundongos , Nefrite/induzido quimicamente , Nefrite/metabolismo , Nefrite/patologia , Índice de Gravidade de Doença , Sinaptofisina/metabolismo
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