RESUMO
When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and "sampled" urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin ß1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed.
Assuntos
Cálculos Renais , Rim , Camundongos , Animais , MacrófagosRESUMO
Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
RESUMO
Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.
Assuntos
Hipertensão , Microglia , Animais , Hipertensão/metabolismo , Camundongos , Neurônios/fisiologia , Potássio/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Pericyte is an indispensable cellular constituent of blood-brain barrier (BBB) and its homeostasis heavily rely on PDGFB-PDGFRß signaling. However, the primary cellular sources of PDGFB in the central nervous system (CNS) are unclear. Microglia is not considered a component of BBB and its role in maintaining BBB integrity in steady state is controversial. In this study, by analyzing transcriptomic data and performing in situ hybridization, we revealed a transition of the primary central PDGFB producers from endothelial cells in newborns to microglia in adults. Acute loss of microglial PDGFB profoundly impaired BBB integrity in adult but not newborn mice, and thus, adult mice deficient of microglial PDGFB could not survive from a sublethal endotoxin challenge due to rampant microhemorrhages in the CNS. In contrast, acute abrogation of endothelial PDGFB had minimal effects on the BBB of adult mice but led to a severe impairment of CNS vasculature in the neonates. Moreover, we found that microglia would respond to a variety of BBB insults by upregulating PDGFB expression. These findings underscore the physiological importance of the microglia-derived PDGFB to the BBB integrity of adult mice both in steady state and under injury.
Assuntos
Barreira Hematoencefálica , Microglia , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Células Endoteliais/metabolismo , Microglia/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismoRESUMO
The kidney is critical in controlling salt and water balance, with the interstitium involved with a variety of components including immune cells in steady state. However, the roles of resident immune cells in kidney physiology are largely unknown. To help unravel some of these unknowns, we employed cell fate mapping, and identified a population of embryo-derived self-maintaining macrophages (SM-MØ) that were independent of the bone marrow in adult mouse kidneys. This kidney-specific SM-MØ population was distinctive from the kidney monocyte-derived macrophages in transcriptome and in their distribution. Specifically, the SM-MØ highly expressed nerve-associated genes; high-resolution confocal microscopy revealed that the SM-MØ in the cortex were in close association with sympathetic nerves and there was a dynamical interaction between macrophages and sympathetic nerves when live kidney sections were monitored. Kidney-specific depletion of the SM-MØ resulted in reduced sympathetic distribution and tone, leading to reduced renin secretion, increased glomerular filtration rate and solute diuresis, which caused salt decompensation and significant weight loss under a low-salt diet challenge. Supplementation of L-3,4-dihydroxyphenylserine which is converted to norepinephrine in vivo rescued the phenotype of SM-MØ-depleted mice. Thus, our findings provide insights in kidney macrophage heterogeneity and address a non-canonical role of macrophages in kidney physiology. In contrast to the well-appreciated way of central regulation, local regulation of sympathetic nerve distribution and activities in the kidney was uncovered.
Assuntos
Rim , Macrófagos , Camundongos , Animais , Rim/fisiologia , Cloreto de Sódio na Dieta , Sistema Nervoso Simpático , Cloreto de Sódio , ÁguaRESUMO
The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8(+) T cell-mediated adaptive immune responses. Aminopeptidases have been linked to the editing of peptides for MHC class I loading, but carboxy-terminal editing is thought to be due to proteasome cleavage. By analysis of wild-type mice and mice genetically deficient in or overexpressing the dipeptidase angiotensin-converting enzyme (ACE), we have now identified ACE as having a physiological role in the processing of peptides for MHC class I. ACE edited the carboxyl terminus of proteasome-produced MHC class I peptides. The lack of ACE exposed new antigens but also abrogated some self antigens. ACE had substantial effects on the surface expression of MHC class I in a haplotype-dependent manner. We propose a revised model of peptide processing for MHC class I by introducing carboxypeptidase activity into the process.
Assuntos
Seleção Clonal Mediada por Antígeno , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptidil Dipeptidase A/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Apresentação de Antígeno/genética , Autoantígenos/imunologia , Autoantígenos/metabolismo , Células Cultivadas , Seleção Clonal Mediada por Antígeno/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Ligação Proteica/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/genética , Linfócitos T/citologia , Linfócitos T/imunologia , Transgenes/genéticaRESUMO
Fibrosis is a relentlessly progressive and irreversible cause of organ damage, as in chronic kidney disease (CKD), but its underlying mechanisms remain elusive. We found that a circular RNA, circPTPN14, is highly expressed in human kidneys with biopsy-proved chronic interstitial fibrosis, mouse kidneys subjected to ischemia/reperfusion (IR) or unilateral ureteral obstruction (UUO), and TGFß1-stimulated renal tubule epithelial cells (TECs). The intrarenal injection of circPTPN14 shRNA alleviated the progression of fibrosis in kidneys subjected to IR or UUO. Knockdown of circPTPN14 in TECs inhibited TGFß1-induced expression of profibrotic genes, whereas overexpressing circPTPN14 increased the profibrotic effect of TGFß1. The profibrotic action of circPTPN14 was ascribed to an increase in MYC transcription. The binding of circPTPN14 to the KH3 and KH4 domains of far upstream element (FUSE) binding protein 1 (FUBP1) enhanced the interaction between FUBP1 and FUSE domain, which was required for the initiation of MYC transcription. In human kidneys (n = 30) with biopsy-proved chronic interstitial fibrosis, the expression of circPTPN14 positively correlated with MYC expression. Taken together these studies show a novel mechanism in the pathogenesis of renal fibrosis, mediated by circPTPN14, which can be a target in the diagnosis and treatment of CKD.
Assuntos
Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Humanos , Camundongos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fibrose , Rim/metabolismo , Proteínas Proto-Oncogênicas c-myc , Insuficiência Renal Crônica/patologia , RNA Circular/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Transcrição GênicaRESUMO
Hypertension ranks the most common risk factor for cardiovascular diseases, and it affects almost one third of adult population globally. Emerging evidence indicates that immune activation is highly involved in the entire progress of hypertension and end organ damage. In addition to immunity, autonomic nervous system, particularly sympathetic nervous system, is one of the most conserved systems to maintain body homeostasis. Immune and sympathetic activities are found simultaneously increased in hypertension, suggesting a synergistic action of these two systems in the progression of this disease. Microglia, the primary immune cells in the central nervous system, have been suggested in the regulation of sympathetic outflow; depletion of microglia alters neuroinflammation and pressor responses in hypertensive models. In this review, we firstly updated the current understanding on microglial ontogeny and functions in both steady state and diseases. Then we reviewed on the interaction between autonomic nervous system and peripheral immunity in hypertension. Microglia bridge the central and peripheral inflammation via regulating the sympathetic nerve activity in hypertension. Future exploration of the molecular linkage of this pathway may provide novel therapeutic angel for hypertension and related cardiovascular diseases.
Assuntos
Sistema Nervoso Autônomo , Hipertensão , Imunidade , Microglia , Animais , HumanosRESUMO
Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant Staphylococcus aureus (MRSA). In contrast, mice overexpressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA and better in vitro killing of MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, P < .0005) in NeuACE neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation and interleukin-1ß release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection.
Assuntos
Resistência à Doença/genética , Imunidade Inata , Neutrófilos/imunologia , Peptidil Dipeptidase A/imunologia , Infecções Estafilocócicas/imunologia , Superóxidos/imunologia , Animais , Membrana Celular , Armadilhas Extracelulares/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Klebsiella pneumoniae , Masculino , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/imunologia , Camundongos , Camundongos Knockout , NADPH Oxidases/genética , NADPH Oxidases/imunologia , Neutrófilos/citologia , Neutrófilos/transplante , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/genética , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Pseudomonas aeruginosa , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/imunologia , Transdução de Sinais , Infecções Estafilocócicas/enzimologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/prevenção & controle , Superóxidos/metabolismoRESUMO
BACKGROUND AND PURPOSE: Hypertension is the major risk factor for stroke. Recent work unveiled that hypertension is associated with chronic neuroinflammation; microglia are the major players in neuroinflammation, and the activated microglia elevate sympathetic nerve activity and blood pressure. This study is to understand how brain homeostasis is kept from hypertensive disturbance and microglial activation at the onset of hypertension. METHODS: Hypertension was induced by subcutaneous delivery of angiotensin II, and blood pressure was monitored in conscious animals. Microglial activity was analyzed by flow cytometry and immunohistochemistry. Antibody, pharmacological chemical, and recombinant cytokine were administered to the brain through intracerebroventricular infusion. Microglial depletion was performed by intracerebroventricular delivering diphtheria toxin to CD11b-diphtheria toxin receptor mice. Gene expression profile in sympathetic controlling nucleus was analyzed by customized qRT-PCR array. RESULTS: Transforming growth factor-ß (TGF-ß) is constitutively expressed in the brains of normotensive mice. Removal of TGF-ß or blocking its signaling before hypertension induction accelerated hypertension progression, whereas supplementation of TGF-ß1 substantially suppressed neuroinflammation, kidney norepinephrine level, and blood pressure. By means of microglial depletion and adoptive transfer, we showed that the effects of TGF-ß on hypertension are mediated through microglia. In contrast to the activated microglia in established hypertension, the resting microglia are immunosuppressive and important in maintaining neural homeostasis at the onset of hypertension. Further, we profiled the signature molecules of neuroinflammation and neuroplasticity associated with hypertension and TGF-ß by qRT-PCR array. CONCLUSIONS: Our results identify that TGF-ß-modulated microglia are critical to keeping brain homeostasis responding to hypertensive disturbance.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Hipertensão/imunologia , Microglia/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Transferência Adotiva , Angiotensina II/toxicidade , Animais , Pressão Sanguínea/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Antígeno CD11b , Toxina Diftérica , Citometria de Fluxo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/fisiopatologia , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Norepinefrina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Sistema Nervoso Simpático , Transcriptoma , Fator de Crescimento Transformador beta1/imunologia , Vasoconstritores/toxicidadeRESUMO
Antigen processing and presentation through the MHC class II pathway is critical for activating T helper cells. Angiotensin-converting enzyme (ACE) is a carboxyl peptidase expressed by antigen-presenting cells. By analysis of ACE null (knockout), wild-type, and ACE-overexpressing (ACE10) mice and the antigen-presenting cells derived from these mice, we found that ACE has a physiological role in the processing of peptides for MHC class II presentation. The efficiency of presenting MHC class II epitopes from ovalbumin (OVA) and hen egg lysosome is markedly affected by cellular ACE levels. Mice overexpressing ACE in myeloid cells have a much more vigorous CD4+ T-cell and antibody response when immunized with OVA. ACE is present in the endosomal pathway where MHC class II peptide processing and loading occur. The efficiency of MHC class II antigen presentation can be altered by ACE overexpression or ACE pharmacological inhibition. Thus, ACE is a dynamic participant in processing MHC class II peptides. Manipulation of ACE expression by antigen-presenting cells may prove to be a novel strategy to alter the immune response.
Assuntos
Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Células Cultivadas , Camundongos , Camundongos Knockout , Ovalbumina/imunologia , Ovalbumina/metabolismo , Peptidil Dipeptidase A/imunologia , Peptidil Dipeptidase A/metabolismoRESUMO
Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension.
Assuntos
Pressão Arterial , Hipertensão/enzimologia , Túbulos Renais/enzimologia , NG-Nitroarginina Metil Éster , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , Cloreto de Sódio na Dieta , Angiotensina II/metabolismo , Animais , Modelos Animais de Doenças , Canais Epiteliais de Sódio/metabolismo , Regulação Enzimológica da Expressão Gênica , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/fisiopatologia , Túbulos Renais/fisiopatologia , Fígado/enzimologia , Camundongos Transgênicos , Natriurese , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/genética , Eliminação Renal , Sistema Renina-Angiotensina/genética , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Fatores de TempoRESUMO
RATIONALE: Chronic inflammation is a major contributor to the progressive pathology of hypertension, and T-cell activation is required for the genesis of hypertension. However, the precise role of myeloid cells in this process is unclear. OBJECTIVE: To characterize and understand the role of peripheral myeloid cells in the development of hypertension. METHODS AND RESULTS: We examined myeloid cells in the periphery of hypertensive mice and found that increased numbers of CD11b(+)Gr1(+) myeloid cells in blood and the spleen are a characteristic of 3 murine models of experimental hypertension (angiotensin II, L-NG-nitroarginine methyl ester, and high salt). These cells express surface markers and transcription factors associated with immaturity and immunosuppression. Also, they produce hydrogen peroxide to suppress T-cell activation. These are characteristics of myeloid-derived suppressor cells (MDSCs). Depletion of hypertensive MDSCs increased blood pressure and renal inflammation. In contrast, adoptive transfer of wild-type MDSCs to hypertensive mice reduced blood pressure, whereas the transfer of nicotinamide adenine dinucleotide phosphate oxidase 2-deficient MDSCs did not. CONCLUSION: The accumulation of MDSCs is a characteristic of experimental models of hypertension. MDSCs limit inflammation and the increase of blood pressure through the production of hydrogen peroxide.
Assuntos
Pressão Sanguínea , Hipertensão/imunologia , Células Mieloides/imunologia , Nefrite/imunologia , Transferência Adotiva , Angiotensina II , Animais , Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Peróxido de Hidrogênio/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Tolerância Imunológica , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Células Mieloides/transplante , NADPH Oxidase 2 , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NG-Nitroarginina Metil Éster , Nefrite/metabolismo , Nefrite/fisiopatologia , Nefrite/prevenção & controle , Transdução de Sinais , Sódio na Dieta , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de TempoRESUMO
Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors.
Assuntos
Peptidil Dipeptidase A/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , História do Século XX , Humanos , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/história , Polimorfismo Genético , Estrutura Terciária de Proteína , Renina/fisiologiaRESUMO
The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.
Assuntos
Hipertensão/metabolismo , Rim/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Peptidil Dipeptidase A/fisiologia , Angiotensina II/metabolismo , Animais , Pressão Sanguínea , Taxa de Filtração Glomerular , Hipertensão/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/química , Natriurese , Óxido Nítrico/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Renina/sangue , Simportadores/metabolismoRESUMO
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which accumulate in cancer, infection and chronic inflammation. These cells suppress T-cell function and the immune response. Angiotensin-converting enzyme (ACE) is a peptidase that is now known to regulate aspects of myelopoiesis. Here, we show that ACE expression correlates with myeloid maturation in vitro. Forced ACE overexpression in monocytic cells reduces the generation of MDSCs. In vivo, mice with a genetic change resulting in myeloid cell ACE overexpression have reduced numbers of blood and splenic MDSCs in a tumor model and in a model of chronic inflammation induced by complete Freund's adjuvant. In contrast, ACE-null mice produce large numbers of MDSCs during chronic inflammation. Macrophages from mice with myeloid ACE overexpressing are more pro-inflammatory and have more tumor-killing activity than cells from wild-type mice. Thus, manipulating myeloid ACE activity can interfere with MDSC development and the maturation of myeloid cells.
Assuntos
Células Progenitoras Mieloides/fisiologia , Mielopoese , Peptidil Dipeptidase A/metabolismo , Animais , Melanoma Experimental/enzimologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Progenitoras Mieloides/enzimologia , FenótipoRESUMO
Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.
Assuntos
Células Precursoras de Granulócitos/enzimologia , Células Precursoras de Granulócitos/imunologia , Imunidade Celular/genética , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Animais , Camundongos , Camundongos KnockoutRESUMO
PURPOSE OF REVIEW: This review presents novel findings regarding the renal angiotensin-converting enzyme (ACE) and its role in blood pressure (BP) control. RECENT FINDINGS: The textbook flow diagram of the renin-angiotensin system (RAS) shows the pulmonary endothelium as the main source of the ACE that converts angiotensin I to angiotensin II. However, ACE is made in large quantities by the kidneys, which raises the important question of what precisely is the function of renal ACE? Recent studies in gene-targeted mice indicates that renal ACE plays a dominant role in regulating the response of the kidney to experimental hypertension. In particular, renal ACE and locally generated angiotensin II affect the activity of several key sodium transporters and the induction of sodium and water retention resulting in the elevation of BP. SUMMARY: New experimental data link the renal ACE/angiotensin II pathway and the local regulation of sodium transport as key elements in the development of hypertension.
Assuntos
Pressão Sanguínea , Hipertensão/enzimologia , Rim/enzimologia , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , Angiotensina II/metabolismo , Animais , Água Corporal/metabolismo , Humanos , Hipertensão/fisiopatologia , Rim/fisiopatologia , Transdução de Sinais , Sódio/metabolismo , Equilíbrio Hidroeletrolítico , Desequilíbrio Hidroeletrolítico/enzimologia , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
The existence of a complete and functional renin-angiotensin system along the nephron is widely recognized. However, its precise role in blood pressure control and, by extension, hypertension is still uncertain. While most investigators agree that overexpressing RAS components along the nephron results in hypertension, two important issues remain: whether the local RAS works as a separate entity or represents an extension of the systemic RAS and whether locally generated angiotensin II has specific renal effects on blood pressure that are distinct from systemic angiotensin II. This review addresses these issues while emphasizing the unique role of local angiotensin II in the response of the kidney to hypertensive stimuli and the induction of hypertension.
Assuntos
Angiotensina II/biossíntese , Pressão Sanguínea/fisiologia , Hipertensão/metabolismo , Rim/metabolismo , Sistema Renina-Angiotensina/fisiologia , Animais , Humanos , Hipertensão/fisiopatologiaRESUMO
While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice overexpress ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-ß protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD.