Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

Chan, Loretta Y.Y.; Leung, Joseph C.K.; Lai, Kar Neng

doi:10.1007/s10157-004-0324-9

Cited by 23 publications

(17 citation statements)

References 39 publications

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“…A substantial body of experimental and clinical data support the role of apoptosis in the pathogenesis of inflammatory tissue injury in critical illness including acute lung injury and ARDS, myocardial infarction, and renal and gastrointestinal tract failure dysfunction in sepsis (52,(70)(71)(72). Although apoptosis is vital in many physiologically important processes, either inappropriate activation or inhibition of apoptosis can lead to disease, either because cells have prolonged survival (ongoing inflammation) or because they die prematurely and produce structural and functional changes in normal tissue.…”

Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Suzuki

Moraes

Vachon

et al. 2005

Am J Respir Cell Mol Biol

123

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Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1-activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1-dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

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Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Suzuki

Moraes

Vachon

et al. 2005

Am J Respir Cell Mol Biol

123

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“…Much attention has recently been focused on inflammatory injuries generated by a positive feedback loop in tubular epithelial cells (TEC) ultimately leading to renal failure [4]. Although pharmacological blockade of the renin angiotensin system (RAS) has become the therapeutic mainstay of tubulointerstitial injury in various glomerular diseases including IgAN, a complete blockade of the RAS with the present dose regimen may not be always possible.…”

Section: Introductionmentioning

confidence: 99%

Additive effect of PPAR-γ agonist and ARB in treatment of experimental IgA nephropathy

et al. 2010

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Our recent in vitro study demonstrated peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist potentiated the anti-inflammatory effect of angiotensin receptor blocker (ARB) in tubular epithelial cell under milieu mimicking IgA nephropathy (IgAN). Here we studied the therapeutic effect of combining a PPAR-γ agonist, rosiglitazone (Ros), with an ARB, losartan (Los), in experimental IgAN induced in Lewis rats by oral and intravenous immunization with bovine gamma-globulin (BGG). The rats were randomly divided into six groups: control, IgAN, IgAN with unilateral nephrectomy (IgAN/1K), and IgAN/1K receiving Ros, Los, or Ros + Los. Medication was given 1 week after nephrectomy until killing. Rats developing IgAN had hematuria, mesangial hypercellularity with IgA deposition, glomerular damage, and tubulointerstitial infiltration of CD25+ leukocytes accompanied by increased renal expression of TGF-β, AngII receptor subtype-1 (ATR1) and ICAM-1. The renal histopathology, albuminuria, and renal expression of TGF-β, ATR1 and ICAM-1 worsened with unilateral nephrectomy. Ros or Los reduced the renal expression of PCNA, TGF-β, ATR1, and ICAM-1 in IgAN rats with nephrectomy. Despite no difference between rats treated with monotherapy, combined therapy offered additive effect with decreased renal expression of TGF-β, ATR1 and ICAM-1 and attenuation of renal injury. Our animal study suggests combined PPAR-γ agonist and ARB holds promise for future therapy for IgAN.

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“…Recently, Sekiguchi et al [21 ]and Chan et al [22] reported that angiotensin II can lead to inflammatory responses through an NF-ĸB-dependent pathway, and that angiotensin II induces an increase in TGF-β in vascular smooth muscles and in mesangial cells [23, 24]. In this context, ARB has been shown to reduce fibrosis in a large number of disease models [25].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Receptor Blockade Ameliorates Mesangioproliferative Glomerulonephritis in Rats through Suppression of CTGF and PAI-1, Independently of the Coagulation System

Liu

Shimizu

Ito‐Ihara

et al. 2006

Nephron Exp Nephrol

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Background: Previously we observed that the coagulation system promotes matrix protein accumulation through transforming growth factor (TGF)-β and connective tissue growth factor (CTGF) expression in rat mesangioproliferative glomerulonephritis (MsPGN). Angiotensin II receptor blockers (ARBs) are known to suppress matrix accumulation in experimental MsPGN. In the present study, we investigated whether ARB suppresses MsPGN through inhibition of these profibrotic cytokines, and in relation to coagulation and fibrinolytic systems. Methods: MsPGN was induced in Wistar rats by intravenous injection of anti-Thy-1.1 monoclonal antibody, OX-7. As an ARB, olmesartan was orally administered in rat feed from the day of OX-7 injection (day 0) to day 8, when rats were sacrificed and kidney specimens were collected. The degrees of cellular proliferation, matrix production, coagulation factors, and inhibitory factor of fibrinolysis were evaluated. Results: Although blood pressure did not change in the normal, disease control, or treatment groups, the amount of urinary protein was significantly decreased in the ARB-treated groups, compared with the disease control group (p < 0.05). α-Smooth muscle actin expression was suppressed significantly in the treatment groups (p < 0.001). Blue-staining areas of trichrome, the number of proliferating cell nuclear antigen (PCNA)- or ED-1-positive cells, fibronectin and plasminogen activator inhibitor type 1 in glomeruli significantly decreased in the treatment groups (p < 0.05, respectively); however, fibrin-related antigen and factor V depositions were not suppressed in the treatment groups. Conclusions: These results suggest that the ARB drug would ameliorate MsPGN in vivo, at least partly through CTGF and plasminogen activator inhibitor type 1 suppression, and independently of the local coagulation system in glomeruli.

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Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

Cited by 23 publications

References 39 publications

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Additive effect of PPAR-γ agonist and ARB in treatment of experimental IgA nephropathy

Angiotensin II Receptor Blockade Ameliorates Mesangioproliferative Glomerulonephritis in Rats through Suppression of CTGF and PAI-1, Independently of the Coagulation System

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