Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy

Mezzano, Sergio; Droguett, Alejandra; Burgos, M. Eugenia; Ardiles, Leopoldo; Flores, Claudio; Aros, Claudio; Caorsi, I; Vío, Carlos P.; Ruíz-Ortega, Marta; Egido, Jesús

doi:10.1046/j.1523-1755.64.s86.12.x

Cited by 168 publications

(139 citation statements)

References 46 publications

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“…Only a very low level of expression of AT 2 R is detected in the adult kidney (Shanmugam et al 1995, Ozone et al 1997. AT 2 R is re-expressed, however, in proximal tubules after ischaemia (Kontogiannis & Burns 1998) and in human diabetic nephropathy (Mezzano et al 2003). We have previously reported the expression of AT 2 R in IRPTCs (Tang et al 1995).…”

Section: Discussionmentioning

confidence: 96%

Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells

Hsieh¹,

Fustier²,

Wei³

et al. 2004

Journal of Endocrinology

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We reported previously that insulin inhibits the stimulatory effect of high glucose on the expression of angiotensinogen (ANG) gene in both rat immortalized renal proximal tubular cells (IRPTCs) and non-diabetic rat renal proximal tubular cells (RPTCs), but has no effect in diabetic rat RPTCs. In the present study we investigated whether hyperglycaemia-induced resistance to the insulininduced inhibition of expression of the ANG gene is mediated via the generation of reactive oxygen species (ROS) in RPTCs. Rat IRPTCs were cultured for 2 weeks in high-glucose (25 mM) or normal-glucose (5 mM) medium plus angiotensin II (Ang II) with or without a superoxide scavenger (tiron), or inhibitors of: NADPH oxidase (diphenylene iodinium, DPI), Ang II type 1 and 2 receptors (losartan and PD123319), angiotensinconverting enzyme (perindopril), protein kinase C (GF 109203X), or glutamine:fructose-6-phosphate aminotransferase (azaserine). Cellular generation of ROS, and ANG and renin mRNA levels were assessed by lucigenin assay and specific reverse transcriptase-PCR respectively. Phosphorylation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) was evaluated by western blotting. Prolonged exposure of IRPTCs to high concentrations of glucose or Ang II evoked generation of ROS and resistance to the insulin-induced inhibition of expression of the ANG gene and of p44/42 MAPK phosphorylation. Co-incubation of IRPTCs with tiron, DPI, losartan, PD123319, perindopril, GF 109203X or azaserine prevented ROS generation, restoring the inhibitory action of insulin on ANG gene expression and on p44/42 MAPK phosphorylation. In conclusion, our studies demonstrate that blockade of both ROS generation and activation of the intrarenal renin-angiotensin system improves the inhibitory action of insulin on ANG gene expression in IRPTCs in conditions of high glucose.

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Section: Discussionmentioning

confidence: 96%

Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells

Hsieh¹,

Fustier²,

Wei³

et al. 2004

Journal of Endocrinology

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“…We studied patients under clamped euglycaemic conditions and using a controlled dietary preparation to isolate the effect of filtration status without the influence of acute hyperglycaemia, renal dysfunction or albuminuria [6]. Under these conditions, urinary factors that are associated with either chemotaxis or inflammation/fibrosis were elevated in DM-H [40][41][42]. Our results suggest that high intraglomerular pressure may provide a mechanistic link between factors that cause hyperfiltration, such as hyperglycaemia-induced renin angiotensin system activation [43], and renal inflammation, leading to the onset of clinical disease.…”

Section: Discussionmentioning

confidence: 99%

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

et al. 2013

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Aims/hypothesis High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus. Methods Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFR INULIN ], n=28) or normofiltration (n=21) and healthy control individuals (n=18).Results Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA 1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165±9 vs 113±2 and 116±4 ml min, respectively, p< 0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p<0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophagederived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colonystimulating factor (p≤0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p<0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p<0.01). Conclusions/interpretation Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.

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“…Angiotensin II modulates the immune response via the production of NF-κB in the cytoplasm of mature phagocytes, resulting in the transcription of inflammatory cytokines and chemokines, including IL-1beta, IL-6, IFN-gamma and TNF-alpha, and IL-8, MCP-1 and CAM-1, respectively. [8][9][10] Angiotensin-converting enzyme inhibitors reduce the expression of monocyte chemo-attractant protein-1 and concomitant macrophage plaque infiltration in animal models of atherosclerosis. 11 In patients with carotid artery disease, the angiotensin receptor blocker irbersartan inhibits metalloproteinase activity, as well as T-cell and macrophage infiltration in the vascular wall.…”

Section: Introductionmentioning

confidence: 99%

Increased Angiotensin II Type 1 Receptor Expression in Temporal Arteries from Patients with Giant Cell Arteritis

et al. 2009

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Link to publication Citation for published version (APA): Dimitrijevic, I., Malmsjö, M., Andersson, C., Rissler, P., & Edvinsson, L. (2009). Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis. Ophthalmology, 116(5), 990-996. DOI: 10.1016990-996. DOI: 10. /j.ophtha.2008 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ___________________________________________ LUP Lund University PublicationsInstitutional Repository of Lund University __________________________________________________ This is an author produced version of a paper published inOphthalmology. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the published paper: Angiotensin II is a vasoactive peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT 1 ) and type 2 (AT 2 ) receptors in GCA. ParticipantsTen patients with GCA and ten control patients, who were clinically suspected of having GCA but were diagnosed as not having GCA, were included. MethodsImmunohistochemistry, using anti-AT 1 and anti-AT 2 antibodies, was performed on formalinfixed and paraffin-embedded temporal arteries. Main outcome measuresAT 1 and AT 2 receptor immunostaining intensity was quantified. ResultsHematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia, internal elastic lamina degeneration and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT 1 3 receptor staining was primarily observed in the medial layer of the temporal arteries, and was higher in the patients with GCA than in the control patients. This was a result of increased AT 1 receptor immunostaining of both vascular smooth muscle cells and of infiltrating inflammatory cells. Only faint immunostaining was seen for AT 2 receptors, primarily in the endothelial cells, and to a lesser extent on the smooth muscle cells. Immunostaining with antibodies for the AT 2 receptor was similar in the patients with GCA and in controls. ConclusionsThese results suggest that AT 1 receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a non-corticosteroid alternative for the treatment of GCA.4

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Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy

Cited by 168 publications

References 46 publications

Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells

Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Increased Angiotensin II Type 1 Receptor Expression in Temporal Arteries from Patients with Giant Cell Arteritis

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