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`Journal of nepnrology
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` OMYSITSaera0 ogeneeve IS Wak GreeTe
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`
`
`JNEPHROL2011; 24(01)
`
`teASata
`
`Cfo{
`
`Sees
`
` 1 Nf
`|
`
`
`Vol. 24 © No. 1
`January-February 2011
`
`www.sin-italy.org
`www.jnephrol.com
`
`
`THOROUGH CRITICAL APPRAISALS
`
`Epidemiology and pathophysiology ofleft ventricular
`abnormalities in chronic kidney disease: a review
`Giovanni Cerasola, Emilio Nardi, Alessandro Palermo,
`Giuseppe Mulé, Santina Cottone
`
`Dietary acid load and rapid progression to end-stage renal disease
`of diabetic nephropathy in Westernized South Asian people
`Else van den Berg, Frédérique A.P. Hospers, Gerjan Navis,
`Marielle FE. Engberink, Elizabeth J. Brink, Johanna M. Geleijnse,
`Marleen A. van Baak, Rijk O.B. Gans, Stephan J.L. Bakker
`
`1
`
`11
`
`REVIEW
`Renal epithelioid angiomyolipoma: a malignant disease
`free autine
`48 )
`Seema Varma, Shilpi Gupta, Jotica Talwar,
`Frank Forte, Meekoo Dhar
`
`Inflammation in the pathophysiologyof essential hypertension
`Fabrizio Montecucco, Aldo Pende,
`Alessandra Quercioli, Francois Mach
`
`free online
`
`23
`
`Achieving effective pain relief in patients with
`chronic kidney disease: a review of analgesicsin renal failure
`Shobhana Nayak-Rao
`
`35
`
`ORIGINAL ARTICLES
`
`The managementofleft ventricular systolic dysfunction
`in patients with advanced chronic kidney disease
`Vera Dounaevskaia, Andrew T. Yan, David Charytan, Laura DiMeglio,
`Howard Leong-Poi, Abdul Al-Hesayen, Marc B. Goldstein, Ron Wald
`
`The effect of anemia andleft ventricular geometric patterns
`on renal disease progressionin type 2 diabetic nephropathy
`Sung Jin Moon, Ki Sun Bae, Hyeong Cheon Park, Jwa Kyung Kim,
`Jung Tak Park, Jung Eun Lee, Se Joong Rim, Sung Kyu Ha
`
`Urinary monocyte chemotactic protein 1: markerof renal function
`decline in diabetic and nondiabetic proteinuric renal disease
`Roberta Camilla, Soumeya Brachemi, Vincent Pichette, Pierre Cartier,
`Alexandra Laforest-Renald, Tara MacRae, Francois Madore, Stéphan Troyanov
`
`Characterization of renal hemodynamic and structural alterations
`in rat models of renal impairment: role of renal sympathoexcitation
`Ibrahim M. Salman, Omar Z. Ameer, MunavvarA. Sattar,
`Nor A. Abdullah, Mun F. Yam, Hafsa S. Najim, Muthanna F. Abdulkarim,
`Ghassan Z. Abdullah, Gurjeet Kaur, Md. Abdul Hye Khan, Edward J. Johns
`
`41
`
`50
`
`60
`
`68
`
`© SocietaItaliana di Nefrologia
`areeri
`
`

`

`JNEPHROL 2011; 24(01)
`
`
`ORIGINAL ARTICLES
`
`Hypercalcemia secondary to persistent hyperparathyroidism
`in kidney transplant patients:
`analysis after a year with cinacalcet
`Rita Guerra, Ingrid Auyanet, Ernesto J. Fernandez,
`Miguel Angel Pérez, Elvira Bosch, Ana Ramirez,
`Santiago Suria, Maria Dolores Checa
`
`Daniela Bandic-Pavlovic, Petar Kes
`
`Effect of a single hemodialysis session
`on endothelial dysfunction
`Prabhakar Reddy Errakonda, Ramakrishna Paladugu,
`AparnaR.Bitla, Suchitra M. Musturu, Jayaseelan Lakshman,
`Srinivasa Rao V.L.N. Pemmaraju, Sivakumar Vishnubhotla
`
`Bone morphogenetic protein-7 expression is down-regulated
`in human clear cell renal carcinoma
`Nikolina Basic-Jukic, Tvrtko Hudolin, Margareta Radic-Antolic,
`Marijana Coric, Renata Zadro, Zeljko Kastelan, Josip Pasini,
`
`free outline
`
`78
`
`free online
`
`83
`
`91
`
`gree online
`
`98
`
`106
`
`112
`
`119
`
`Vitamin D supplementation and recombinant
`humanerythropoietin utilization
`in vitamin D-deficient hemodialysis patients
`Victoria A. Kumar, Dean A. Kujubu, John J. Sim,
`Scott A. Rasgon, Philip S. Yang
`
`Effect of IL-11 on glomerular expression of TGF-beta and
`extracellular matrix in nephrotoxic nephritis in Wistar Kyoto rats
`Maria Stangou, Gurjeet Bhangal, Ping-Chin Lai, Jennifer Smith,
`James C. Keith Jr, Joseph J. Boyle, Charles D. Pusey,
`Terence Cook, Frederick W.K. Tam
`
`Gypenosidesinhibit renal fibrosis by regulating expression
`of related genesin rats with unilateral ureteral obstruction
`Yong Zhang, Jian-E Zhang, Hou-Qin Xiao,
`Ping-Yong Wu, Shou-Jun Bai
`
`High-sodium diet promotesa profibrogenic reaction
`in normalrat kidneys:effects of Tempol administration
`Maria Inés Roson, Silvana Lorena Della Penna, Gabriel Cao,
`Susana Gorzalczany, Marcela Pandolfo, Carolina Cerrudo,
`Belisario E. Fernandez, Jorge E. Toblli
`
`
`CASE REPORTS
`
`Life-threatening hypercalcemiain patients with
`rhabdomyolysis-inducedoliguric acute renalfailure
`Giorgio Graziani, Albania Calvetta, David Cucchiari,
`Serenella Valaperta, Alessandro Montanelli
`
`428
`
`© Societa Italiana di Nefrotogia
`
`(errrerrreeerrrerreeeeccaearnerreeeeereneeeeeeeeeeeeeeeeeeeeean
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`JNEPHROL 2011; 24(01): 106-111
`aTSNa
`
`SUBJECTS AND METHODS
`
`Phospho-p38 MAPK
`
`For this study, we used renal tissue from previously re-
`ported experiments (10, 12).
`
`Experiment 1: natural history of NTN in Wistar
`Kyoto rats
`
`NTN was inducedin male Wistar Kyoto (WKY)rats weigh-
`ing 200-250 g by intravenous administration of 0.1 mL
`rabbit anti-rat glomerular basement membrane (GBM)
`nephrotoxic serum (12). Rats were sacrificed at different
`time points between 2.5 hours and 44 days. Three to 4
`rats were studied at each time point.
`
`Immunostaining for p-p38 MAPK wasperformed on for-
`malin-fixed, paraffin-embedded tissue. The slides were
`incubated overnight with 1:100 of the p-p38 MAPK
`mouse mAb (M 8177, clone p38-TY; Sigma-Aldrich,
`Poole, UK) and then with a peroxidase-conjugated goat
`anti-mouse antibody, for 45 minutes at 4°C. In each rat,
`the numberof positive cells was counted in 25 glom-
`erular sections.
`
`Statistical analysis
`
`All parameters are expressed as mean + standarderror.
`Mann-Whitney U-test was used to comparethe different
`groups; p<0.05 was considered to be significant.
`
`Experiment2: effect of IL-11 treatment on NTN in
`WKYrats
`
`RESULTS
`
`RhIL-11 supplied by Wyeth/Genetics Institute (Cam-
`bridge, MA, USA) was administered intraperitoneally to
`16 NTN rats, in either 800 pg (n=6) or 1,360 ug (n=10)
`daily. The first treatment was given 2 hours before in-
`duction of NTN, and then oncedaily for 6 days. Vehicle-
`treated rats (n=8) received 0.2 mL of vehicle, intraperito-
`neally, on the same schedule. Rats were culled on day
`6 (10).
`tmmunohistochemistry
`TGF-f1, a-SMAandfibronectin
`
`immunohistochemistry on cryostat sections was per-
`formed for TGF-B1 (polyclonal goat anti-mouse, sc-
`146-G; Santa-Cruz Biotechnology, Santa Cruz, CA,
`USA), a-SMA (mouse anti-human mAb, clone 1A4,
`Mog51; DAKO, Ely, UK) and fibronectin (mouse anti-
`human mAb, OBT0082; Oxford Biotechnology, Oxford,
`UK). The polyclonal anti-TGF-B1 antibody wasdiluted in
`0.1% bovine serum albumin (BSA) / phosphate-buffered
`saline (PBS) + 0.1% polyoxyethylene sorbitan monolau-
`rate (Tween 20) + 10% normal rabbit serum, and slides
`were incubated overnight at 4°C. The other antibodies
`were diluted in 0.1% BSA/PBS. Theintensity of glom-
`erular staining was assessed by semiquantitative score,
`on a scale of 0 to 3, with the observer unaware of the
`details of the groups. Periglomerular staining was ex-
`pressed as percentage of glomeruli affected. In 6 rats of
`each group, there was enough tissue for immunostain-
`ing on cryostat sections.
`
`Experiment 1: TGF-B1, «-SMA,fibronectin and p-p38
`MAPKexpression during the natural history of NTN
`
`TGF-B1 was first detected in the glomerular mesan-
`gium on day 6 and in the tubulointerstitium on day 11,
`both increasing during disease progression. a-SMA, a
`marker for myofibroblasts, was detected on day 4 in
`the periglomerular area, and on day6 in both periglom-
`erular and mesangial regions, which increased further
`at the later stages of the disease. Fibronectin wasfirst
`detected in the glomerular mesangium on day 4 andin
`the periglomerular area on day 6. The intensity of p-p38
`MAPK expression was increasedinitially only 5 hours
`after nephrotoxic serum (NTS) administration, reduced
`subsequently during days 2-4, but increased again on
`day 6. At these time points, staining was nuclear in the
`mesangial and parietal epithelial cells and cytoplasmic in
`tubular epithelial cells. Representative results are shown
`in Figure 1.
`
`Experiment2: effect of rhiL-11 treatment
`
`The intensity of TGF-B1 glomerular expression was re-
`duced from 2.04 + 0.1 semi-quantitative score in the ve-
`hicle group to 0.4 + 0.1 (p<0.005) in rats treated with high-
`dose rhiL-11.
`Both glomerular and periglomerular expression of a-SMA
`and fibronectin were reduced by high-dose IL-11 treat-
`ment (a-SMAfrom 1.5 + 0.1 to 0.4 + 0.1 semiquantitative
`score, p<0.01, and from 92% + 2.5% to 9.6% + 2% of
`
`:
`is materia,
`© 2011 Socielébrain rNefeiaia"Issn 1121-8428
`Subject US Copyright Laws
`
`107
`
`

`

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`Stangouet al: Anti-TGF effect of IL-11 in glomerulonephritis
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`- Fibrotic processes in nephrotoxic nephritis (NTN).
`Fig. 1
`A) TGF-B1 was not detected in the normalrat tissue. B) In-
`creased glomerular TGF-B1 expression was detected after
`induction of NTN. C) In normal control kidneys, «-SMA was
`detected only in vascular smooth muscle cells. D) Increasein
`glomerular and periglomerular «-SMA staining was detected
`after induction of NTN. E) Fibronectin was not detected in
`normalcontrol kidneys. F) Glomerular and periglomerular ex-
`pression of fibronectin was increasedafter induction of NTN.
`G) Only very low levels of phospho-p38 MAPK (p-p38 MAPK)
`were detected in normal control rats. H) Increased expres-
`sion of p-p38 MAPKafter induction of NTN.
`
`Fig. 2 - Treatment with rhIL-11 in nephrotoxic nephritis
`(NTN). Increased renal expression of TGF-B1 (A), x-SMA
`(C), fibronectin (E) and p-p38 MAPK(G) was detectedin ve-
`hicle-treated rats 6 days after induction of NTN. Treatment
`with high-dose rhIL-11 (1,360 pg daily) reduced expression
`of TGF-B1 (B), «-SMA (D) and fibronectin (F). There was
`also a slight reduction of p-p38 MAPK(H) in the glomeruli
`of IL-11-treated rats.
`
`glomeruli, p<0.01, respectively, and fibronectin from 1.5
`+ 0.1 to 0.6 + 0.1 semiquantitative score, p<0.02, and
`from 94% + 1.9% to 26% + 4.9% of glomeruli, p<0.005,
`respectively) (Figs. 2 and 3). Treatment with low-doseIL-
`11 did not affect significantly the expression of TGF-B1,
`a-SMAand fibronectin (data not shown).
`
`In rats receiving IL-11 there was a slight reduction in the
`numberof glomerular and tubular cells expressing p-p38
`MAPK,andin the intensity of the staining, compared to
`vehicle group, but this reduction did not reach statistical
`significance (Figs. 2 and 3). The effect of low-dose IL-11
`on renal p-p38 MAPK wasnotstudied.
`
`108
`
`pe
`
`© 2011 SocieltasGPhBRSRETIssN 1121-8428
`atthe NLM and may
`Subject US Copyright Laws
`
`

`

`JNEPHROL 2011; 24(01): 106-111
`(renneTOSTEEN
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`I-11
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`IL-11
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`© 2011 SocietalitinanatarieircieGaRiNSGN 1121-3428
`atthe NLMband may be
`Subject US Copyright Laws
`
`109
`
`of sclerotic lesions (18, 19). Adenoviral gene transfer of
`soluble TGF-B1 receptorIl reduced the number of «-SMA
`(+) cells and amelioratedinterstitial fibrosis in NTN (20). In
`our study, x-SMA was expressedinitially in the periglom-
`erular area on day 4; however, its periglomerular as well as
`mesangial expression was increased on day 6, whenthefi-
`bronectin expression wasalso increased. The periglomeru-
`lar x-SMA up-regulation can be attributed to myofibrablast
`formation. Activated myofibroblasts become hypertrophic
`and secrete extracellular matrix proteins, and this may lead
`to glomerulosclerosis,fibrous crescent formation and tubu-
`lointerstitial fibrosis (18).
`Phosphorylation and activation of p38 MAPK was noticed
`very early, only 5 hours after NTS induction, but mostinter-
`estingly, its activation happened in a repeated way. P-p38
`MAPK expression was increased 5 hours after induction
`of NTN, reduced to normallevels during days 2-4 and re-
`lapsed on day 6. Transientinactivation of p-p38 MAPK may
`be dueto its interaction with MAPK phosphatases (MKPs).
`MKPsare a family of protein phosphatases, which are re-
`sponsible for the dephosphorylation and inactivation of
`MAPKs. MKPsare activated simultaneously with MAPKs
`(20, 21), and they may be responsible for p-p38 MAPK in-
`activation.
`In the present study this inactivation seemed
`to be transient, because p38 MAPKwasreactivated later,
`probably as a result of cytokine and growth factor produc-
`tion. To our knowledge, this dual activation of p88 MAPK
`has not been described previously; however, more specific
`studies are necessary to investigate it further.
`Fig. 3 - Treatment with rhiL-11 in nephrotoxic nephritis (NTN).
`There wasonly a small reduction in renal p-p38 MAPK ex-
`Treatment with high-dose IL-11 reduced expression of glom-
`pression in IL-11-treated rats. These results suggest that
`erular TGF-B1 (A), glomerular &-SMA (C), periglomerular
`glomerular expression of TGF-B1 andinfiltration/transfor-
`«-SMA (D), glomerular fibronectin (E) and_periglomerular
`fibronectin (F) in comparison with vehicle-treated rats. The
`mation of myofibroblasts may proceed independently of
`reduction in glomerular p-p38 MAPK(B) wasnotsignificant.
`p-p38 MAPK,this is in accordance with a previous study,
`which showed that p-p38 MAPK wasnot the only down-
`stream signalling intermediate in the pathway from TGF-B1
`to &-SMA (22). Also, administration of a TGF-$1 receptor
`inhibitor (SD-208) resulted in the attenuation myofibroblast
`transformation of lung fibroblasts, an effect that could not
`be achieved by a p38 MAPKinhibitor(SD 282) (23).
`In this study, we have shown that treatment with a high
`In our previous report, both high and low dosesof IL-11
`dose of IL-11 reduced glomerular expression of TGF-f1,
`reduced proteinuria and glomerularfibrinoid necrosis, but
`&-SMA and fibronectin in NTN. To our knowledge, the
`
`present study is the first demonstration that administration hadadifferent effect on glomerular macrophages(10). Dai-
`of rhIL-11 may alleviate glomerular expression of TGF-B1
`ly treatment with a high dose (1,360 ug) of rhIL-11 reduced
`activation of myofibroblasts and extracellular matrix depo-
`the numberofinfiltrating macrophages; a low dose (800
`sition in experimental glomerulonephritis.
`ig) of rhIL-11 reduced only the numberof activated mac-
`In the kidney, myofibroblasts may derive from perivascular
`rophages, not the total number of macrophages. Based on
`smooth muscle cells, pericytes and interstitial fibroblasts,
`this reduction, the anti-TGF effect of IL-11 could be attrib-
`after stimulation by cytokines such as TGF-B1 and IL-18
`uted to its anti-inflammatory properties, a mechanism that
`(15-17). Myofibroblasts are implicated in the development
`has also been described for other agents (24). However,
`
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`Stangouet al: Anti-TGF effect of IL-11 in glomerulonephritis
`(cancersmRATTTALENETETTTTSecOOCNTaraaaaea,
`
`the fact that low-dose rhIL-11 was enough to reduce IL-
`1B production, and macrophage activity, but not TGF-81,
`a-SMA and fibronectin expression, makes the position
`more complicated. It seems that administration of rhIL-11
`has the potential to reduce inflammation, even when giv-
`en at lower doses, but this anti-inflammatory effect is not
`enough to justify its anti-TGF effect, which requires higher
`dosage,andis also independent from p38 MAPK dephos-
`phorylation and inactivation. One of the speculationsis that
`the reduction in the number of glomerular macrophagesis
`needed to reduce the TGF-B1 expression. Further work is
`neededto investigate this possibility.
`Findings of the present study suggest that IL-11 has a
`dose-dependenteffect in glomerular expression of TGF-B1,
`myofibroblastdifferentiation and extracellular matrix depo-
`sition in NTN. This finding may beof relevance to develop-
`ment of possible new applicationsof IL-11 and also novel
`treatment strategies in patients with glomerulonephritis.
`
`Financial support: This work was supported by a research project
`grant from Kidney Research UK. M.S. received a research project
`grant from the Greek Rena! Association.
`
`Conflict of interest statement: James C. Keith Jr is an employee of
`Wyeth Research, Cambridge, MA, USA.
`
`Address for correspondence:
`Maria Stangou, MD
`Nephrology DepartmentAristotle University
`Hippokration Hospital
`50 Papanastasiou Street
`Thessaloniki, Greece
`mstangou@math.com
`
`REFERENCES
`
`1.
`
`3.
`
`Trepicchio WL, Dorner AJ. Interleukin-11: a gp130 cytokine.
`Ann N Y Acad Sci. 1998;856:12-21.
`2. Miiller-Newen G. The cytokine receptor gp130: faithfully pro-
`miscuous. Sci STKE. 2003;2003:PE40.
`Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-
`Newen G, Schaper F. Principles of
`interleukin (IL)-6-
`type cytokine signalling and its regulation. Biochem J.
`2003;374:1-20.
`Schwertschlag US, Trepicchio WL, Dykstra KH, Keith JC,
`Turner KJ, Dorner AJ. Hematopoietic,
`immunomodula-
`tory and epithelial effects of
`interleukin-11. Leukemia.
`1999;13:1307-1315.
`Kurzrock R, Cortes J, Thomas DA,Jeha§, Pilat S, Talpaz M.
`Pilot study of low-dose interleukin-11 in patients with bone
`marrowfailure. J Clin Oncol. 2001;19:4165-4172.
`Ragni MV, Jankowitz RC, Chapman HL, et al. A phase II
`prospective open-label escalating dosetrial of recombinant
`interleukin-11 in mild von Willebrand disease. Haemophilia.
`2008; 14:968-977.
`Schmitz B, Thiele J, Witte O, Kaufmann R, WickenhauserC,
`FischerR. Influence of cytokines (IL-1 alpha,IL-3, IL-11, GM-
`CSF) on megakaryocyte-fibroblast interactions in normal hu-
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`man bone marrow. Eur J Haematol. 1995;55:24-32.
`Peterson RL, WangL, Albert L, Keith JC Jr, Dorner AJ. Mo-
`lecular effects of recombinant humaninterleukin-11 in the
`HLA-B27 rat modelof inflammatory bowel disease. Lab In-
`vest. 1998;78:1503-1512.
`Tang W, Geba GP, Zheng T, et al. Targeted expression of IL-
`11 in the murine airway causes lymphocytic inflammation,
`bronchial remodeling, and airways obstruction. J Clin Invest.
`1996;98:2845-2853.
`10. Lai PC, Cook HT, Smith J, Keith JC Jr, Pusey CD, Tam FW.
`Interleukin-11 attenuates nephrotoxic nephritis in Wistar
`Kyoto rats. J Am Soc Nephrol. 2001:12:2310-2320.
`Lai PC, Smith J, Bhangal G, et al. Interleukin-11 reduces
`renal injury and glomerular NF-kappa B activity in murine
`experimental glomerulonephritis. Nephron Exp Nephrol.
`2005;101:146-154,
`12, Tam FW, Smith J, Morel D,et al. Development of scarring
`and renal failure in a rat model of crescentic glomerulone-
`phritis. Nephrol Diai Transplant. 1999;14:1658-1666.
`13. Martin MM, BuckenbergerJA, Jiang J, et al. TGF-beta1 stim-
`ulates human AT1 receptor expression in lung fibroblasts by
`cross talk between the Smad, p38 MAPK, JNK, and PI3K
`signaling pathways. Am J Physiol Lung Cell Mol Physiol.
`2007;293:790-799.
`14. Kutz SM, Hordines J, McKeown-LongoPu, Higgins PJ. TGF-
`
`11.
`
`110
`
`© 2011 BusietattaliahwatMotetegia - ISSN 1121-8428
`atthe NLM and maybe
`Subject US Copyright Laws.
`
`

`

`JNEPHROL2011; 24(01): 106-111
`
`
`
`Lemnaaramaaniemnareaerentennn
`
`15.
`
`16.
`
`17,
`
`18.
`
`19.
`
`20.
`
`B1-induced PAI-1 gene expression requires MEKactivity and
`cell-to-substrate adhesion. J Cell Sci. 2001;114:3905-391 4.
`Vesey DA, Cheung CW,Cuttle L, Endre ZA, Gobe G, Johnson
`DW.Interleukin-1 beta induces humanproximaltubule cell in-
`jury, alpha-smooth muscle actin expression and fibronectin
`production. Kidney Int. 2002;62:31-40.
`Kondo S, Kagami S, Urushihara M, et al. Transforming growth
`factor-beta1 stimulates collagen matrix remodeling through
`increased adhesive and contractive potential by humanrenal
`fibroblasts. Biochim Biophys Acta. 2004;1693:91-100.
`Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R.
`Fibroblasts in kidney fibrosis emerge via endothelial-to-mesen-
`chymaltransition. J Am Soc Nephrol. 2008;19:2282-2287.
`Goumenos D, Tsomi K, latrou C, et al. Myofibroblasts and
`the progression of crescentic glomerulonephritis. Nephrol
`Dial Transplant. 1998;13:1652-1661.
`Roberts IS, Burrows C, Shanks JH, Venning M, McWilliam
`LJ. Interstitial myofibroblasts: predictors of progression in
`membranous nephropathy. J Clin Pathol. 1997;50:123-127.
`Zhou A, Ueno H, Shimomura M, et al. Blockade of TGF-beta
`action ameliorates renal dysfunction and histologic progres-
`sion in anti-GBM nephritis. Kidney Int. 2003;64:92-101.
`
`21.
`
`22.
`
`23.
`
`24.
`
`Dickinson RJ, Keyse SM. Diverse physiological functions
`for dual-specificity MAP kinase phosphatases. J Cell Sci.
`2006;119:4607-4615.
`Ding Q, Gladson CL, Wu H, Hayasaka H, Olman MA. Fo-
`cal adhesion kinase (FAK)-related non-kinase inhibits
`myofibroblast differentiation through differential MAPK
`activation in a FAK-dependent manner. J Biol Chem.
`2008;283:26839-26849.
`Kapoun AM, Gaspar NJ, WangY, et al. Transforming growth
`factor-beta receptor type 1 (TGFbetaR)) kinase activity but
`not p38 activation is required for TGFbetaRi-induced myofi-
`broblast differentiation and profibrotic gene expression. Mol
`Pharmacol. 2006;70:518-531.
`Nagatoya K, MoriyamaT, KawadaN, et al. Y-27632 prevents
`tubulointerstitial fibrosis in mouse kidneys with unilateral ure-
`teral obstruction. Kidney Int. 2002;61:1684-1695.
`
`Received: July 14, 2009
`Revised: February 22, 2010
`Accepted: March 01, 2010
`
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`atthe NLM and may be
`Subject US Copyright Laws
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