Evidence for Abundant Presence of Chymase-Positive Mast Cells in the Kidneys of Patients with Immunoglobulin A Nephropathy: Effect of Combination Therapy with Prednisolone and Angiotensin II Receptor Blocker Valsartan

Konishi, Yoshio; Morikawa, Takashi; Okada, Noriyuki; Maeda, Isseki; Kitabayashi, Chizuko; Yoshioka, Katsunobu; Okumura, Michiaki; Nishiyama, Akira; Ueda, Makiko; Miyazaki, Mizuo; Imanishi, Masahito

doi:10.1291/hypres.31.1517

Cited by 11 publications

(8 citation statements)

References 16 publications

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“…However, no measurable differences were found within the time frame examined, suggesting that blood pressure regulation does not contribute to the observed aggravation. Our findings extend previous observations suggesting that human chymase and mMCP-4 act as an alternate pathway to ACE for Ang II production in vivo, as shown in experimental and human nephropathies (46–49). Histological analysis of kidney tissue sections also revealed a partial inhibition of type I collagen deposition in mMCP-4–deficient mice, an intriguing finding that differed from the known ability of mMCP-4 to trigger MMP-9 activity, which degrades collagen (9).…”

Section: Discussionsupporting

confidence: 91%

Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis

Scandiuzzi

Beghdadi

Daugas

et al. 2010

The Journal of Immunology

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Mast cells exert protective effects in experimental antiglomerular basement membrane-induced glomerulonephritis (GN), yet the responsible mediators have not been identified. In this study, we investigated the role of mouse mast cell protease (mMCP)-4, the functional homolog of human chymase, using mMCP-4–deficient mice. Compared with wild type animals, mMCP-4–deficient mice exhibited lower proteinuria, blood creatinine, and blood urea nitrogen levels, indicating an aggravating role of mMCP-4. Kidney histology confirmed less severe renal damage in mMCP-4–deficient mice with reduced deposits, glomerular and interstitial cellularity, and fibrosis scores. High amounts of mMCP-4 were detected in renal capsules, but not in the whole kidney, from wild type mice. Its expression in renal capsules was markedly decreased after GN induction, suggesting that locally released enzyme by degranulated mast cells could contribute to the functional and physiopathological hallmarks of GN. Supporting a proinflammatory role, glomerular and interstitial macrophage and T cell infiltration, levels of proinflammatory TNF and MCP-1 mRNA, and the expression of the profibrotic peptide angiotensin II together with type I collagen were markedly downregulated in kidneys of mMCP-4−deficient mice. We conclude that mMCP-4 chymase, contrary to the global anti-inflammatory action of mast cells, aggravates GN by promoting kidney inflammation. These results highlight the complexity of mast cell-mediated inflammatory actions and suggest that chymase inhibition may represent a novel therapeutic target in GN.

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Section: Discussionsupporting

confidence: 91%

Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis

Scandiuzzi

Beghdadi

Daugas

et al. 2010

The Journal of Immunology

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“…Increased chymase expression has been observed in humans with diabetic nephropathy (DN), 12,13 IgA nephropathy, 14,15 autosomal dominant polycystic kidney disease, 16 and hypertensive nephropathy 17 suggesting a central role of chymase in many forms of kidney disease in humans. Interestingly, in patients with DN, the number of renal chymase-positive mast cells is positively correlated with the severity of DN, 18 suggesting that degranulation of mast cells promotes renal inflammation and fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Direct Evidence for Intrarenal Chymase-Dependent Angiotensin II Formation on the Diabetic Renal Microvasculature

Park

Bivona²,

Ford³

et al. 2013

Hypertension

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Our previous work supports a major role for angiotensin-converting enzyme (ACE)-independent intrarenal angiotensin (ANG) II formation on microvascular function in type II diabetes. We tested the hypothesis that there is a switch from renal vascular ACE-dependent to chymase-dependent ANGII formation in diabetes. The in vitro juxtamedullary afferent arteriole (AA) contractile responses to the intrarenal conversion of the ACE-specific, chymase-resistant ANGI peptide ([Pro10]ANGI) to ANGII were significantly reduced in kidneys of diabetic (db/db) compared to control (db/m) mice. AA responses to the intrarenal conversion of the chymase-specific, ACE-resistant ANGI peptide ([Pro11, DAla12]ANGI) to ANGII were significantly enhanced in kidneys of diabetic compared to control mice. AA diameters were significantly reduced by 9 ± 2, 15 ± 3 and 24 ± 3% of baseline in diabetic kidneys in response to 10, 100, and 1000 nmol/L [Pro11, DAla12]ANGI, respectively and the responses were significantly attenuated by angiotensin type 1 (AT1) receptor or chymase-specific (JNJ-18054478) inhibition. [Pro11, DAla12]ANGI did not produce a significant AA vasoconstriction in control kidneys. Chymase inhibition significantly attenuated ANGI-induced AA vasoconstriction in diabetic, but not control kidneys. Renal vascular mMCP-4 (mouse mast cell protease-4; chymase)/β-actin mRNA expression was significantly augmented by 5.1 ± 1.4 fold; while ACE/β-actin mRNA expression was significantly attenuated by 0.42 ± 0.08 fold in diabetic compared to control tissues. In summary, intrarenal formation of ANGII occurs primarily via ACE in the control, but via chymase in the diabetic vasculature. In conclusion, chymase-dependent mechanisms may contribute the progression of diabetic kidney disease.

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“…The number of mast cells closely correlates with the severity of tubulointerstitial disease in renal diseases, including IgA nephropathy [31, 32], primary and secondary glomerulonephritis [18, 19, 33, 34], diabetic nephropathy [35,36], hypertensive nephropathy [26] and allograft rejection [16, 20, 37, 38]. Mast cell accumulation is also inversely correlated with a decline in glomerular filtration rate and disease progression [31, 34, 39-41].…”

Section: Mast Cell Density Correlates With Renal Tubulointerstitial Dmentioning

confidence: 99%

“…Chymase-positive mast cells are increased in human renal allografts with chronic rejection 37 and in the setting of IgA nephropathy [32], and correlate with the severity of interstitial fibrosis and intra-renal vascular resistance. In children with crescentic glomerulonephritis, chymase-positive mast cells also correlate with tubolointerstitial fibrosis and with loss of renal function [33].…”

Section: Chymase-positive Mast Cells Localize To Sites Of Kidney Fibrmentioning

confidence: 99%

“…In children with crescentic glomerulonephritis, chymase-positive mast cells also correlate with tubolointerstitial fibrosis and with loss of renal function [33]. Interestingly, IgA nephropathy patients treated with valsartan and prednisolone for two months, compared with prednisolone alone, were observed to experience a significant reduction in the number of chymase-positive mast cells on repeat renal biopsy accompanied by improved renal parenchymal circulation [32], suggesting that blocking Ang II actions by inhibiting its AT 1 receptor could possibly attenuate recruitment of mast cells to the kidney. This hypothesis, however, needs to be tested.…”

Section: Chymase-positive Mast Cells Localize To Sites Of Kidney Fibrmentioning

confidence: 99%

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Impact of Mast Cell Chymase on Renal Disease Progression

Wasse¹,

Naqvi²,

Husain³

2012

CHYR

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Chymase, a serine protease found in mast cell granules, is released into the interstitium following injury or inflammation. Chymase is the primary ACE-independent pathway of angiotensin II formation, and also functions to activate TGF-beta and other promoters of extracellular matrix degradation, thereby playing a role in tissue remodeling. In the diseased kidney, chymase-containing mast cells markedly increase and their density correlates with tubulointerstitial fibrosis severity. Studies in humans support the pathologic role of chymase in diabetic nephropathy, while animal studies form the basis for the importance of increased chymase-dependent angiotensin II formation in progressive hypertensive, diabetic and inflammatory nephropathies. Moreover, humans with kidney disease express chymase in diseased blood vessels in concordance with significantly elevated plasma chymase levels. Conversely, specific chymase inhibitors attenuate angiotensin II production and renal fibrosis in animal models, suggesting their potential therapeutic benefit in human nephropathy, where chymase-containing mast cells accumulate and contribute to progressive disease.

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Evidence for Abundant Presence of Chymase-Positive Mast Cells in the Kidneys of Patients with Immunoglobulin A Nephropathy: Effect of Combination Therapy with Prednisolone and Angiotensin II Receptor Blocker Valsartan

Cited by 11 publications

References 16 publications

Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis

Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis

Direct Evidence for Intrarenal Chymase-Dependent Angiotensin II Formation on the Diabetic Renal Microvasculature

Impact of Mast Cell Chymase on Renal Disease Progression

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