Renal fibroblasts are sensitive to growth-repressing and matrix-reducing factors from activated lymphocytes

Kitamura, Asuka; Kitamura, Masanori; Nagasawa, Ryo; Maruyama, Naoki; Mitarai, Tetsuya; Takahashi, Tadashi C.; Isoda, Kikuo

doi:10.1111/j.1365-2249.1993.tb05934.x

Cited by 4 publications

(2 citation statements)

References 19 publications

(10 reference statements)

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“…In our model of AAN, PTEC and interstitial cells both expressed TGF‐β, 17,19 confirming Yang’s data on human cases of the acute phase of AAN 36 . This persistent inflammation leads to resident fibroblast activation 68,72–76 …”

Section: Discussionsupporting

confidence: 88%

“…36 This persistent inflammation leads to resident fibroblast activation. 68,[72][73][74][75][76] To summarize, the present data support the concept that innate and adaptive immunity is involved in the deleterious evolution of primarily non-immune kidney disease. Histological criteria of AAN diagnosis might be revisited taking into consideration the presence of interstitial inflammation.…”

Section: Itsupporting

confidence: 80%

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Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?

et al. 2010

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Aims:The histological features of aristolochic acid nephropathy (AAN) consist of paucicellular interstitial fibrosis, severe tubular atrophy, and almost intact glomeruli with media lesions of interlobular arteries. As an early phase of interstitial inflammation preceded peritubular fibrosis in the rat model of AAN, the aim was to investigate the presence of inflammatory cells in human AAN. Methods and results: Reports of confirmed cases and case series of AAN were reviewed in terms of interstitial inflammation and found to have very conflicting results. This prompted us to search for and characterize inflammatory cells within the native kidneys provided from four end-stage AAN patients. Prior aristolochic acid exposure was attested by the intrarenal presence of the typical aristolactam I-derived DNA adduct. Besides the tubulointerstitial lesions usually seen in the cortex, a massive infiltration of macrophages, T and B lymphocytes was detected by immunohistochemistry in the medullary rays and in the outer medullae with some extension to the upper cortical labyrinth. Conclusions: In parallel with histological findings reported in the rat model, inflammatory cells are present preferentially in the interstitium of the medullary rays and of the outer medulllae in renal interstitium from human AAN cases, even in the terminal stages. Further studies must be undertaken to determine the respective roles of innate and adaptive immunity in the progression of AAN.

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Section: Discussionsupporting

confidence: 88%

Section: Itsupporting

confidence: 80%

Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?

et al. 2010

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Gene transfer of metalloproteinase transin induces aberrant behavior of cultured mesangial cells

Kitamura

Shirasawa

Maruyama

1994

Kidney International

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The aim of the present study is to clarify whether the cellular expression of a matrix-degrading metalloproteinase, transin, alters the behavior of cultured mesangial cells (MCs). The cDNA encoding rat transin was introduced into rat MCs and transcribed under the control of a Rous sarcoma virus promoter. The resulting transfectants were then investigated for cell shape, migration, proliferation, and expression of genes associated with matrix metabolism. Northern blot analysis routinely detected the transin transcript in two separate transfectants, MeTRN2 and MeTRN5. Transin expression was strong in MeTRN2, moderate in MeTRN5, but absent in mock transfectants. Immunoblot analysis revealed that these transin transfectants synthesized 59 and 62 kDa molecules, which correspond to transin gene products. Casein digestion assay detected enhanced proteolytic activity in MeTRN2 and MeTRN5. Microscopically, the transfected cells were somewhat elongated with accentuated margins compared with mock transfectants. [3H]-thymidine uptake studies revealed accelerated growth of the transfectants on a plastic substratum as well as within gel matrix. The migration of the transfectants into gel matrix was also significantly enhanced compared with that of mock transfectants. No obvious alteration, however, was found in transcripts of procollagen alpha 1(IV), laminin B2, or the metalloproteinase inhibitor TIMP. We hypothesize that the metalloproteinase transin has a potential for affecting the behavior of MCs and contributing to the pathogenesis of glomerular injury.

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SPARC is expressed in renal interstitial fibrosis and in renal vascular injury

Pichler¹,

Hugo²,

Shankland³

et al. 1996

Kidney International

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Tubulointerstitial inflammation and fibrosis are critical determinants for renal function and prognosis in a variety of human nephropathies. Yet, the pathophysiology of the injury remains obscure. We investigated the expression of SPARC (secreted protein acidic and rich in cysteine) by immunohistochemistry and in situ hybridization in experimental models characterized by tubulointerstitial fibrosis and matrix expansion in rats. SPARC is a secreted glycoprotein that has been demonstrated to affect cellular interaction with matrix proteins, modulate cell proliferation, bind to and/or inhibit growth factors such as PDGF and bFGF, and regulate angiogenesis. Interstitial expression of SPARC was most prominent in passive Heyman nephritis (PHN), chronic cyclosporine A (CsA) nephropathy, and the remnant kidney model and, to a lesser extent, in angiotensin II (Ang II)-infused animals. SPARC protein and mRNA were substantially increased at sites of tubulointerstitial fibrosis/matrix expansion. In the PHN model, SPARC protein was expressed by interstitial fibroblasts that also produced alpha-smooth muscle actin ("myofibroblasts") and correlated both temporally (r = 0.97) and spatially with sites of type I collagen deposition. Interstitial cell proliferation preceded the development of interstitial fibrosis, and maximal SPARC expression (d15) coincided with the initial decline in interstitial proliferation. In the Ang II-infusion model, which is characterized by arteriolopathy and tubulointerstitial injury, an increase in SPARC protein and mRNA was also seen in injured blood vessels. SPARC was shown to be expressed by vascular smooth muscle cells and also by cells in the adventitia of hypertrophied arteries. In summary, SPARC was transiently expressed by interstitial fibroblasts at sites of tubulointerstitial injury and fibrosis, and by smooth muscle cells and cells in the adventitia of injured arteries in the Ang II-model. In addition to its proposed role in extracellular matrix deposition. the antiproliferative properties of SPARC might contribute to the resolution of interstitial fibroblast proliferation in the PHN model.

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Renal fibroblasts are sensitive to growth-repressing and matrix-reducing factors from activated lymphocytes

Cited by 4 publications

References 19 publications

Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?

Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?

Gene transfer of metalloproteinase transin induces aberrant behavior of cultured mesangial cells

SPARC is expressed in renal interstitial fibrosis and in renal vascular injury

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