Contribution of mast cells to the tubulointerstitial lesions in IgA nephritis

Ehara, Takashi; Shigematsu, Hidekazu

doi:10.1046/j.1523-1755.1998.00159.x

Cited by 80 publications

(93 citation statements)

References 27 publications

(20 reference statements)

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“…Intensity of specific mRNA bands was quantified by computer-assisted densitometry, normalized to the intensity of the 28S bands on the ethidium bromide-stained blots, and expressed as PAI-1/28S ratio (B, D, F, and H, mean Ϯ SD of three separate experiments). *P Ͻ 0.001 versus 0 h. extent of the infiltration was directly and significantly correlated with the degree of interstitial fibrosis (22).…”

Section: Discussionmentioning

confidence: 85%

“…Mast cell infiltration has often been observed in chronic inflammation leading to tissue fibrosis in different organs, including lung, liver, skin, and kidney (21)(22)(23)(24). In particular, the presence of these immune cells was recently described within the interstitial space in IgAN by different authors (22). Interestingly, the E), and thrombin (G), harvested at the indicated time points and then total RNA was extracted.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the presence of these immune cells has been described within the interstitial space in IgAN (22). Interestingly, the extent of the infiltration was directly and significantly correlated with the degree of interstitial fibrosis (22). Although mast cells have been suggested to play a pivotal role in the pathogenesis of fibrotic processes, the mechanisms underlying their potential fibrogenic action is still largely unclear.…”

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confidence: 99%

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Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-β, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-β expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN. E-mail: g.grandaliano@nephro.uniba.it

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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“…For example, sustained stimulation of AT2 receptors by the ARB-induced ANG II may upregulate the bradykinin production, 10,15,19,20 while ACE-I accumulates bradykinin by directly inhibiting its degradating enzyme. Furthermore, in renal disease, where chymase-containing mast cells prevail, 22 the non-ACE-dependent ANG II formation may be enhanced within the kidney, but not in systemic vascular beds; in contrast, ARB could disrupt the ANG II activity. Alternatively, the elevated urinary NO x may simply reflect a consequence of renal protection in the long-term treatment.…”

Section: Discussionmentioning

confidence: 99%

Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease

2003

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Although the angiotensin receptor antagonist (ARB) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/ nitrate (NO x ) excretion in hypertensive (140 and/or 90 mmHg) patients with chronic renal disease (serum creatinineo265 (range, 44-265) lmol/l or creatinine clearance430 (range, 30-121) ml/min). Patients with mild (o1 g/day; range, 0.4-1.0) and moderate proteinuria (41 g/day; range, 1.1-6.9) were randomly assigned to ACE-I-and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44 7 6% reduction in proteinuria (from 2.7 7 0.5 to 1.5 7 0.4 g/day, n ¼ 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 7 0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23 7 8%, n ¼ 13), but a 41 7 6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NO x excretion were observed with ACE-I (from 257 7 70 to 1111 7 160 lmol/day) and ARB (from 280 7 82 to 723 7 86 lmol/day), the ARB-induced increase in NO x excretion was smaller than that by ACE-I (Po0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuriareducing effect was observed with ACE-I, which paralleled the increase in urinary NO x excretion. Conversely, ARB decreased proteinuria and increased urinary NO x excretion gradually. These time course-dependent changes in proteinuria and urinary NO x may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin.

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“…Mast cells also produce a variety of cytokines that mediate delayed-type hypersensitivity (DTH) (9) and are key components of the pathogenesis of proliferative GN, injurious (e.g., TNF), and protective (e.g., IL-4) (20 -22). Experimental and human GN studies have demonstrated a strong correlation between the number of interstitial mast cells and severity of interstitial injury (19,(23)(24)(25). In inflammatory renal injury induced in rats by subtotal nephrectomy, a significant infiltration of mast cells in the tubulointerstitium was accompanied by increased IL-8, SCF, and TGF-␤ expression (26).…”

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confidence: 99%