Effects of Renin-Angiotensin System Blockade on Macrophage Infiltration in Patients with Hypertensive Nephrosclerosis

Imakiire, Toshihiko; Kikuchi, Yasufumi; Yamada, Muneharu; Kushiyama, Taketoshi; Higashi, Keishi; Hyodo, Naomi; Yamamoto, Kojiro; Oda, Takashi; Suzuki, Shigenobu; Miura, Soichiro

doi:10.1291/hypres.30.635

Cited by 21 publications

(19 citation statements)

References 24 publications

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“…48,49 Indeed, inflammatory gene signatures were significantly altered in NSC glomeruli (Supplemental Table S3, see http://ajp.amjpathol.org) including major histocompatibility class I and II genes, interleukins, and chemokines. Although glomerular inflammatory cell infiltrates have been observed in NSC, 50 they are not a prominent feature of glomerular NSC. 11,12 In addition, it should be noted that the expression of "inflammatory" genes cannot be directly equated with inflammatory infiltrates, as some of these genes could be regulated on intrinsic glomerular cells, for which our observations with CXCR4 on podocytes may serve as example.…”

Section: Discussionmentioning

confidence: 98%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

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In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

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Section: Discussionmentioning

confidence: 98%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

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“…Endothelial injury may result in switching from the endothelial anticoagulant phenotype to the procoagulant phenotype, which is characterized by decreased fibrinolytic activity, including the upregulation of plasminogen activator inhibitor-1, exposure of the thrombogenic subendothelial surface, platelet activation, and cellular activation with upregulation of adhesion molecules, chemokines, cytokines, and transcription factors [30][31][32]. Infiltration of macrophages and foam cell differentiation with the production of several cytokines also develops in the glomeruli after endothelial cells and podocyte injury [33][34][35][36]. Combined, all these factors may contribute to podocyte damage.…”

Section: Discussionmentioning

confidence: 99%

A case of secondary focal segmental glomerulosclerosis associated with malignant hypertension

et al. 2012

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Focal segmental glomerulosclerosis (FSGS) is associated with various clinicopathological conditions, including hypertension. We report here a case of secondary FSGS associated with malignant hypertension. A 33-yearold man with a 1-month history of visual impairment and headache visited the Department of Ophthalmology at our hospital and was found to have hypertensive retinopathy and severe hypertension (230/160 mmHg). He was referred to our department based on suspected renal dysfunction. His blood pressure on admission was 250/130 mmHg. Physical examination and laboratory tests revealed hypertensive cardiac dysfunction, focal brain edema, renal dysfunction (serum creatinine, Cr 7.07 mg/dl, blood urea nitrogen, BUN 49.9 mg/dl), massive proteinuria (10.7 g/day), and thrombotic microangiopathy. Funduscopy showed exudate, hemorrhage, and papilledema. The cause of secondary hypertension could not be identified. He was treated for primary malignant hypertension, but required hemodialysis 3 days after admission due to anuria. Treatment with antihypertensive agents resulted in the gradual recovery of renal function, although heavy proteinuria continued with nephrotic syndrome. Renal biopsy performed 1 month after admission showed features of malignant nephrosclerosis with secondary FSGS. Hemodialysis was discontinued following further improvement in renal function and the most recent laboratory tests showed proteinuria 1.8 g/day and persistent renal dysfunction (BUN 36.5 mg/dl, Cr 3.14 mg/ dl). Malignant hypertension may cause various injuries, including glomerular endothelial and epithelial cell injuries in glomerular hypertension and hyperfiltration, increase of the renin-angiotensin-aldosterone system, and endothelialepithelial interaction, resulting in the development of secondary FSGS and heavy proteinuria.

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“…Em humanos hipertensos, foi observado o aumento do espaço de Virchow-Robin, local este pré-linfático com riqueza em células do sistema imune que permite a comunicação entre do SNC e o SNP (MARIN-PADILLA; KNOPMAN, 2011).…”

Section: Inflamação E Lesão Em óRgãos Alvounclassified

“…Campbell (2013) descreveu o efeito antiinflamatório dos inibidores da ECA justamente por inibir a ação da angiotensina II, consequentemente ocorre a inibição da atividade pró-inflamatória deste hormônio. Imakiire et al (2007) demonstraram em pacientes humanos que os inibidores da ECA reduzem o infiltrado de macrófagos nos glomérulos.…”

Section: Inibidores Da Enzima Conversora De Angiotensinaunclassified

Importance of Inflammation in Hypertension - Review

et al. 2014

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RESUMO:Componentes do sistema imune inato e adaptativo desempenham uma participação importante na fisiopatologia da hipertensão arterial sistêmica (HAS). A atividade de macrófagos, células dendríticas, linfócitos T e linfócitos B estão associadas a disfunção endotelial e infiltrado inflamatório perivascular nos vasos sanguíneos, nos rins, no encéfalo e coração, alterações estas, intimamente relacionadas com a instalação e desenvolvimento da HAS. A deformação mecânica nas células endoteliais dos vasos sanguíneos, que ocorre durante a elevação da pressão arterial, promove uma cascata de sinalização e eventos que estimulam a liberação e expressão de moléculas de adesão e mediadores inflamatórios que recrutam as células inflamatórias. O óxido nítrico (NO) e as espécies reativas do oxigênio (ERO) são elementos do sistema imune inato, produzidos por macrófagos, que atuam no processo inflamatório desencadeado por alterações mecanoelásticas dos vasos sanguíneos durante a HAS. A resposta imune adaptativa também pode estar presente nestas condições, pois após o aumento da atividade de células da imunidade inata e a presença de ERO, ocorre liberação de mediadores inflamatórios que recrutam as células dendríticas, linfócitos T e linfócitos B. As células inflamatórias e as ERO também sensibilizam o sistema nervoso central (SNC) que resulta em maior atividade do sistema nervoso simpático (SNS) induzindo a vasoconstrição e aumento da volemia. Outros fatores, como a renina, angiotensina II, aldosterona e a liberação de citocinas estão diretamente envolvidas em todos esses processos. Descrever o papel da inflamação na HAS constituiu no objetivo da presente revisão de literatura. Palavras-chaves: Coração. Linfócitos. Macrófagos. Rins IMPORTANCE OF INFLAMMATION IN HYPERTENSION -REVIEW SUMMARY:Components of the innate and adaptive immune system play an important role in the pathophysiology of hypertension (HBP). The activity of macrophages, dendritic cells and lymphocytes are associated with endothelial dysfunction and perivascular inflammatory infiltrate in the blood vessels, kidneys, brain and heart, these changes, closely related to the installation and development of hypertension. The mechanical deformation in endothelial cells of blood vessels that occurs during the elevation of blood pressure, causes a cascade of signaling events and stimulating the expression and release of adhesion molecules and inflammatory mediators that recruit inflammatory cells. Nitric oxide (NO) and reactive oxygen species (ROS) are elements of the innate immune system, produced by macrophages, which act in the inflammatory process triggered by changes deformation in endothelial cells of blood vessels during hypertension. The adaptive immune response may also be present in these conditions, because after the increased activity of cells of innate immunity and the presence of ROS, occurs release of inflammatory mediators that recruit dendritic cells and lymphocytes. Inflammatory cells and ROS also sensitize the central nervous system (CNS) that results ...

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Effects of Renin-Angiotensin System Blockade on Macrophage Infiltration in Patients with Hypertensive Nephrosclerosis

Cited by 21 publications

References 24 publications

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

A case of secondary focal segmental glomerulosclerosis associated with malignant hypertension

Importance of Inflammation in Hypertension - Review

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