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`© Societa Italiana di Nefrologia 2010
`ISSN 1121-8428
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`‘
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`REVIEW
`Renal epithelioid angiomyolipoma: a malignant disease
`gm mane
`18 ‘
`Seema Varma, Shilpi Gupta, Jotica Talwar,
`Frank Forte, Meekoo Dhar
`
`Vol. 24 0 No. 1
`
`January-February 2011
`
`www.sin-italy. org
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`www.jnephrol.com
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`
`Inflammation in the pathophysiologyof essential hypertension
`Fabrizio Montecucco, Aldo Pende,
`
`{nee Mane
`
`23
`
`Alessandra Quercio/i, Francois Mach
`
`Achieving effective pain relief in patients with
`chronic kidney disease: a review of analgesics in renal failure
`Shobhana Nayak-Rao
`
`35
`
`
`ORIGINAL ARTICLES
`
`The management of left ventricular systolic dysfunction
`in patients with advanced chronic kidney disease
`Vera Dounaevskaia, Andrew I Yan, David Charytan, Laura DiMeg/io,
`Howard Leong-Poi, Abdul Al-Hesayen, Marc B. Goldstein, Ron Wald
`
`The effect of anemia and left ventricular geometric patterns
`on renal disease progression in type 2 diabetic nephropathy
`Sung Jin Moon, Ki Sun Bae, Hyeong Cheon Park, Jwa Kyung Kim,
`Jung Tak Park, Jung Eun Lee, Se Joong Him, Sung Kyu Ha
`
`Urinary monocyte chemotactic protein 1: marker of renal function
`decline in diabetic and nondiabetic proteinuric renal disease
`Roberta Cami/Ia, Soumeya Brachemi, Vincent Pichette, Pierre Cartier,
`Alexandra Laforest—Rena/d, Tara MacRae, Francois Madore, Stephan Troyanov
`
`Characterization of renal hemodynamic and structural alterations
`in rat models of renal impairment: role of renal sympathoexcitation
`Ibrahim M. Sa/man, Omar Z. Ameer, Munavvar A. Sattar,
`Nor A. Abdul/ah, Mun F. Yam, Hafsa S. Najim, Muthanna F. Abdulkarim,
`Ghassan Z. Abdul/ah, Gurjeet Kaur, Md. Abdul Hye Khan, Edward J. Johns
`
`41
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`50
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`60
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`68
`
`© Societa Italiana di Nefrologia
`MW
`
`JNEPHROL 2011; 24(01)
`
`1‘ Wlwmuwumm mums .1. Wk
`" c NiliEN'il‘S
`‘ ltnquxMMBWMm'
`
`THOROUGH CRITICAL APPRAISALS
`
`
`
`
`Epidemiology and pathophysiology of left ventricular
`abnormalities in chronic kidney disease: a review
`Giovanni Ceraso/a, Emilio Nardi, Alessandro Palermo,
`Giuseppe Mule, 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, Frederique A.P. Hospers, Gerjan Navis,
`Mariel/e F. Engberink, Elizabeth J. Brink, Johanna M. Ge/eijnse,
`Marleen A. van Baak, Rijk O. B. Gans, Stephan J.L. Bakker
`
`1
`
`11
`
`

`

`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 Perez, Elvira Bosch, Ana Ramirez,
`Santiago Suria, Maria Dolores Checa
`
`Effect of a single hemodialysis session
`on endothelial dysfunction
`Prabhakar Reddy Errakonda, Ramakrishna Paladugu,
`Aparna R. Bit/a, Suchitra M. Musturu, Jayaseelan Lakshman,
`Srinivasa Rao MLN. 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,
`Danie/a Bandic-Pav/ovic, Petar Kes
`
`Vitamin D supplementation and recombinant
`human erythropoietin utilization
`in vitamin D—deficient hemodialysis patients
`Victoria A. Kumar, Dean A. Kujubu, John J. Sim,
`Scott A. Rasgon, Philip S. Yang
`
`Effect of lL—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
`
`Gypenosides inhibit renal fibrosis by regulating expression
`of related genes in rats with unilateral ureteral obstruction
`Yong Zhang, Jian-E Zhang, Hou-Qin Xiao,
`Ping-Yong Wu, Shou-Jun Bai
`
`High—sodium diet promotes a profibrogenic reaction
`in normal rat kidneys: effects of Tempol administration
`Maria Ine’s Roson, Silvana Lorena Della Penna, Gabriel Cao,
`Susana Gorzalczany, Marcela Pandolfo, Carolina Cerrudo,
`Belisario E. Fernandez, Jorge E. Tobi/i
`
`CASE REPORTS
`
`Life—threatening hypercalcemia in patients with
`rhabdomyolysis-induced oliguric acute renal failure
`Giorgio Graziani, Albania Calvetta, David Cucchiari,
`Serene/la Valaperta, Alessandro Montane/li
`
`{we Meme
`
`78
`
`gm mm
`
`83
`
`91
`
`{466 WM
`
`98
`
`106
`
`112
`
`119
`
`128
`
`© Societa Italiana di Nefrologia
`W
`
`

`

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

`

`JNEPHROL 2011; 24(01): 106-111W
`
`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 induced in 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 was performed 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 number of positive cells was counted in 25 glom-
`erular sections.
`
`Statistical analysis
`
`All parameters are expressed as mean 1 standard error.
`Mann-Whitney U-test was used to compare the different
`groups; p<0.05 was considered to be significant.
`
`Experiment 2: effect of lL-1 1 treatment on NTN in
`WKY rats
`
`RESULTS
`
`RhlL-11 supplied by Wyeth/Genetics Institute (Cam-
`bridge, MA, USA) was administered intraperitoneally to
`16 NTN rats, in either 800 ug (n=6) or 1,360 ug (n=10)
`daily. The first treatment was given 2 hours before in—
`duction of NTN, and then once daily 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
`5 (10)-
`
`lmmunohistochemistry
`
`TOT-.57, a_SMA and fibronectin
`
`Immunohistochemistry on cryostat sections was per-
`formed for TGF-B1 (polyclonal goat anti-mouse, sc-
`146—Gi Santa-Cruz Biotechnology, Santa Cruz, CA,
`USA),
`ot—SMA (mouse anti—human mAb, clone 1A4,
`M0851; DAKO, Ely, UK) and fibronectin (mouse anti—
`human mAb, OBT0082; Oxford Biotechnology, Oxford,
`UK). The polyclonal anti-TGF-B1 antibody was diluted in
`o_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. The intensity 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, ct-SMA, fibronectin and p-p38
`MAPK expression 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. or-SMA, a
`marker for myofibroblasts, was detected on day 4 in
`the periglomerular area, and on day 6 in both periglom-
`erular and mesangial regions, which increased further
`at the later stages of the disease. Fibronectin was first
`detected in the glomerular mesangium on day 4 and in
`
`the periglomerular area on day 6. The intensity of p—p38
`
`MAPK expression was increased initially 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.
`
`Experiment 2: effect of rhIL-11 treatment
`
`The intensity of TGF-B1 glomerular expression was re-
`duced from 2.04 w: 0.1 semi—quantitative score in the ve-
`
`hicle group to 0.4 i 0.1 (p<0.005) in rats treated with high-
`dose rhlL-11.
`
`Both glomerular and periglomerular expression of or—SMA
`and fibronectin were reduced by high—dose lL-11 treat—
`
`ment (Oi-SMA from 1.5 i 0.1 to 0.4 :l: 0.1 semiquantitative
`score, p<0.01, and from 92% i 2.5% to 9.6% i 2% of
`
`107
`
`"' mate r'a
`.
`© 2011 Somefi@1211an langfiéitfiff-disw 1121-8428
`may
`Subject; Ui{1e~py‘right Laws
`
`

`

`Stangou et al: Anti—TGF effect of IL-11 in glomeru/onephritis
`
`“.r‘
`
`al.45uswuw31vl
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`- Fibrotic processes in nephrotoxic nephritis (NTN).
`Fig. 1
`A) TGF-B1 was not detected in the normal rat tissue. B) In-
`creased glomerular TGF-B1 expression was detected after
`induction of NTN. C) In normal control kidneys, or-SMA was
`detected only in vascular smooth muscle cells. D) Increase in
`glomerular and periglomerular or-SMA staining was detected
`after induction of NTN. E) Fibronectin was not detected in
`normal control kidneys. F) Glomerular and periglomerular ex-
`pression of fibronectin was increased after 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 MAPK after induction of NTN.
`
`Fig. 2 - Treatment with rhlL-11 in nephrotoxic nephr't's
`(NTN). Increased renal expression of TGF-B1 (A), (XjSMA
`(C), fibronectin (E) and p-p38 MAPK (G) was detected In ve-
`hicle-treated rats 6 days after induction of NTN. Treatment
`with high-dose rhlL-11 (1,360 pg daily) reduced expreSSIon
`of TGF-B1 (B), a-SMA (D) and fibronectin (F). There wa§
`also a slight reduction of p-p38 MAPK (H) in the glomerull
`of lL-11-treated rats.
`
`glomeruli, p<0.01, respectively, and fibronectin from 1.5
`:t 0.1 to 0.6 i 0.1 semiquantitative score, p<0.02, and
`from 94% :l: 1.9% to 26% :t 4.9% of glomeruli, p<0.005,
`respectively) (Figs. 2 and 3). Treatment with low-dose IL—
`
`11 did not affect significantly the expression of TGF—B1,
`a-SMA and fibronectin (data not shown).
`
`in rats receiving IL—11 there was a slight reduction in the
`number of glomerular and tubular cells expressing p—p38
`MAPK, and in 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 was not studied.
`
`1 08
`
`(v.
`
`© 2011 Societa‘EMS atnefiél‘ofi‘éédISSN 1121-8428
`atthe NLM and may
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`JNEPHROL 2011; 24(01): 106-111
`
`of sclerotic lesions (18, 19). Adenoviral gene transfer of
`soluble TGF—B1 receptor || reduced the number of (X-SMA
`(+) cells and ameliorated interstitial fibrosis in NTN (20). In
`our study, Oi-SMA was expressed initially in the periglom-
`erular area on day 4; however, its periglomerular as well as
`
`mesangial expression was increased on day 6, when the fi—
`bronectin expression was also increased. The periglomeru-
`lar or-SMA up-regulation can be attributed to myofibroblast
`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 most inter—
`estingly, its activation happened in a repeated way. P-p38
`MAPK expression was increased 5 hours after induction
`of NTN, reduced to normal levels during days 2-4 and re—
`
`lapsed on day 6. Transient inactivation of p-p38 MAPK may
`be due to its interaction with MAPK phosphatases (MKPS).
`MKPs are a family of protein phosphatases, which are re—
`sponsible for the dephosphorylation and inactivation of
`
`MAPKS. MKPs are 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 MAPK was reactivated later,
`probably as a result of cytokine and growth factor produc—
`tion. To our knowledge, this dual activation of p38 MAPK
`has not been described previously; however, more specific
`studies are necessary to investigate it further.
`There was only a small reduction in renal p—p38 MAPK ex-
`pression in lL-11—treated rats. These results suggest that
`glomerular expression of TGF—B1 and infiltration/transfor-
`mation of myofibroblasts may proceed independently of ,
`p-p38 MAPK, this is in accordance with a previous study,
`which Showed that p-p38 MAPK was not the only down-
`stream signalling intermediate in the pathway from TGF—B1
`to ct—SMA (22). Also, administration of a TGF—B1 receptor
`inhibitor (SD-208) resulted in the attenuation myofibroblast
`transformation of lung fibroblasts, an effect that could not
`
`Fig. 3 - Treatment with rhlL-11 in nephrotoxic nephritis (NTN).
`Treatment with high-dose lL-11 reduced expressnon of glom-
`erular TGF-B1 (A), glomerular 0<_-SMA (C). perlglomerular
`Ot-SMA (D), glomerular fibronectln (E) and periglomerular
`fibronectin (F) in comparison With vehicle-treated rats. The
`reduction in glomerular p-p38 MAPK (B) was not significant.
`
`DISCUSSION
`
`In this study, we have shown that treatment with a high
`dose of lL—11 reduced glomerular expression of TGIF-B1,
`(X-SMA and fibronectin in NTN. To our knowledge, the
`
`be achieved by a p38 MAPK inhibitor(SD 282) (23).
`In our previous report, both high and low doses of lL—11
`reduced proteinuria and glomerular fibrinoid necrosis, but
`
`present study is the first demonstration that administration
`of rhIL—11 may alleviate glomerular expression of TGF-Bl
`activation of myofibroblasts and extracellular matrix depo—
`sition in experimental glomerulonephritis.
`In the kidney, myofibroblasts may derive from perivascular
`smooth muscle cells, pericytes and interstitial fibroblasts,
`after stimulation by cytokines such as TGF—B1 and lL—1B
`
`(15-17). Myofibroblasts are implicated in the development
`
`had a different effect on glomerular macrophages (1 O). Dai-
`|y treatment with a high dose (1,360 ug) of rhlL-11 reduced
`
`the number of infiltrating macrophages; a low dose (800
`ug) of rhlL—11 reduced only the number of activated mac—
`
`rophages, not the total number of macrophages. Based on
`this reduction, the anti-TGF effect of lL-11 could be attrib—
`
`uted to its anti-inflammatory properties, a mechanism that
`has also been described for other agents (24). However,
`
`© 2011 Societ‘afitaaanateirreénaegtaeirssN 1121-8428
`at; the NLM and may be
`So Eject: Uzi Eapy‘right Laws
`
`109
`
`

`

`Stangou et al: Anti-TGF effect of IL-11 in glomerulonephritisW
`
`the fact that low-dose rhlL—11 was enough to reduce IL-
`
`18 production, and macrophage activity, but not TGF-B1,
`O(-SMA and fibronectin expression, makes the position
`
`more complicated. It seems that administration of rhlL-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, and is also independent from p38 MAPK dephos-
`phorylation and inactivation. One of the speculations is that
`the reduction in the number of glomerular macrophages is
`
`needed to reduce the TGF-Bt expression. Further work is
`
`needed to investigate this possibility.
`Findings of the present study suggest that lL—11 has a
`dose—dependent effect in glomerular expression of TGF-B1,
`myofibroblast differentiation and extracellular matrix depo-
`sition in NTN. This finding may be of relevance to develop-
`ment of possible new applications of lL—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. MS. received a research project
`grant from the Greek Renal 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 Department Aristotle University
`Hippokration Hospital
`50 Papanastasiou Street
`Thessaloniki, Greece
`mstangou@math.com
`
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`Received: July 14, 2009
`Revised: February 22, 2010
`Accepted: March 01, 2010
`
`© 2011 SOCietafllta‘fianatairNéfRfiagiafiifiSN 1121-8428
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