Volume 73, Issue 7, Pages (April 2008)

Slides:



Advertisements
Similar presentations
Potential Down-Regulation of Salivary Gland AQP5 by LPS via Cross-Coupling of NF-κB and p-c-Jun/c-Fos  Chenjuan Yao, Nunuk Purwanti, Mileva Ratko Karabasil,
Advertisements

Volume 81, Issue 11, Pages (June 2012)
Volume 62, Pages S12-S22 (December 2002)
Glucocorticoids Augment the Chemically Induced Production and Gene Expression of Interleukin-1α through NF-κB and AP-1 Activation in Murine Epidermal.
ACE Inhibitor Quinapril Reduces the Arterial Expression of NF-κB-Dependent Proinflammatory Factors but not of Collagen I in a Rabbit Model of Atherosclerosis 
Volume 60, Issue 3, Pages (September 2001)
Renin-stimulated TGF-β1 expression is regulated by a mitogen-activated protein kinase in mesangial cells  Y. Huang, N.A. Noble, J. Zhang, C. Xu, W.A.
Volume 81, Issue 11, Pages (June 2012)
Volume 118, Issue 4, Pages (April 2000)
Volume 71, Issue 6, Pages (March 2007)
Phosphoinositide 3-kinase inhibitors protect mouse kidney cells from cyclosporine- induced cell death  E. Sarró, O. Tornavaca, M. Plana, A. Meseguer, E.
Volume 69, Issue 4, Pages (February 2006)
Li-Wen Lai, Kim-Chong Yong, Yeong-Hau H. Lien  Kidney International 
NF-κBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1β-induced and TNF-α-induced chondrocytes  Dr C. Lianxu, Ph.D.,
Requirement of heat shock protein 90 in mesangial cell mitogenesis
Volume 24, Issue 5, Pages (May 2006)
Volume 71, Issue 3, Pages (February 2007)
H.T. Lee, M. Kim, M. Jan, R.B. Penn, C.W. Emala  Kidney International 
Smad7 gene transfer inhibits peritoneal fibrosis
IL-17A is a novel player in dialysis-induced peritoneal damage
Volume 84, Issue 2, Pages (August 2013)
Volume 69, Issue 12, Pages (June 2006)
IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy  J.-A. Moon,
Volume 69, Issue 10, Pages (May 2006)
Renin-stimulated TGF-β1 expression is regulated by a mitogen-activated protein kinase in mesangial cells  Y. Huang, N.A. Noble, J. Zhang, C. Xu, W.A.
R Largo, Ph. D. , M. A Alvarez-Soria, B. S. , I Dı́ez-Ortego, B. S
Volume 68, Issue 3, Pages (September 2005)
Volume 87, Issue 2, Pages (February 2015)
Volume 68, Issue 1, Pages (July 2005)
Akio Horiguchi, Mototsugu Oya, Ken Marumo, Masaru Murai 
Volume 74, Issue 5, Pages (September 2008)
Volume 78, Issue 2, Pages (July 2010)
Volume 81, Issue 3, Pages (February 2012)
Volume 63, Issue 2, Pages (February 2003)
Volume 60, Issue 3, Pages (September 2001)
Volume 80, Issue 12, Pages (December 2011)
Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor  L.D. Alexander, Y. Ding, S. Alagarsamy,
Volume 70, Issue 9, Pages (November 2006)
S100A15, an Antimicrobial Protein of the Skin: Regulation by E
Gene transfer of truncated IκBα prevents tubulointerstitial injury
Ribosomal Protein S3 Gene Silencing Protects Against Cigarette Smoke-Induced Acute Lung Injury  Jinrui Dong, Wupeng Liao, Hong Yong Peh, W.S. Daniel Tan,
The Rho-kinase pathway regulates angiotensin II-induced renal damage
Histamine Enhances the Production of Granulocyte-Macrophage Colony-Stimulating Factor via Protein Kinase Cα and Extracellular Signal-Regulated Kinase.
Noritaka Oyama, Keiji Iwatsuki, Yoshimi Homma, Fumio Kaneko 
Volume 73, Issue 5, Pages (March 2008)
Cyclooxygenase-2 Inhibitor Enhances Whereas Prostaglandin E2Inhibits the Production of Interferon-Induced Protein of 10 kDa in Epidermoid Carcinoma A431 
Volume 70, Issue 2, Pages (July 2006)
Volume 65, Issue 3, Pages (March 2004)
Agonists of Proteinase-Activated Receptor-2 Stimulate Upregulation of Intercellular Cell Adhesion Molecule-1 in Primary Human Keratinocytes via Activation.
P. Harding, L. Balasubramanian, J. Swegan, A. Stevens, W.F. Glass 
Parathyroid hormone–related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2  Juan A Ardura, Ana.
DNA binding of activator protein-1 is increased in human mesangial cells cultured in high glucose concentrations  William A. Wilmer, Fernando G. Cosio 
Volume 61, Issue 6, Pages (June 2002)
Volume 62, Pages S12-S22 (December 2002)
Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy  Carolina Lavoz, Yenniffer Sánchez Matus,
Volume 83, Issue 6, Pages (June 2013)
STAT proteins mediate angiotensin II–induced production of TIMP-1 in human proximal tubular epithelial cells  Xiangmei Chen, Jianzhong Wang, Feng Zhou,
Volume 64, Pages S33-S38 (October 2003)
Volume 122, Issue 1, Pages (January 2002)
Klotho is a target gene of PPAR-γ
Volume 53, Issue 6, Pages (June 1998)
Volume 70, Issue 5, Pages (September 2006)
Lawrence M. Pfeffer, Andrzej T. Slominski 
Lipoxin A4 inhibits connective tissue growth factor-induced production of chemokines in rat mesangial cells  S.-H. Wu, X.-H. Wu, C. Lu, L. Dong, G.-P.
Angiotensin III increases MCP-1 and activates NF-кB and AP-1 in cultured mesangial and mononuclear cells  Marta Ruiz-Ortega, Oscar Lorenzo, Jesus Egido 
Myeloid Differentiation Factor 88 Regulates Basal and UV-Induced Expressions of IL-6 and MMP-1 in Human Epidermal Keratinocytes  Youngae Lee, Hyunjung.
Volume 61, Issue 6, Pages (June 2002)
Naoko Kanda, Shinichi Watanabe  Journal of Investigative Dermatology 
IL-1β induces VEGF, independently of PGE2 induction, mainly through the PI3-K/mTOR pathway in renal mesangial cells  D. Solà-Villà, M. Camacho, R. Solà,
Volume 72, Issue 2, Pages (July 2007)
Presentation transcript:

Volume 73, Issue 7, Pages 835-847 (April 2008) Parathyroid hormone-related protein promotes inflammation in the kidney with an obstructed ureter  D. Rámila, J.A. Ardura, V. Esteban, A. Ortega, M. Ruiz-Ortega, R.J. Bosch, P. Esbrit  Kidney International  Volume 73, Issue 7, Pages 835-847 (April 2008) DOI: 10.1038/sj.ki.5002775 Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 1 PTHrP and PTH1R expression in the obstructed kidney from PTHrP-TG mice and their control littermates. In the kidney of sham-operated mice or the obstructed kidney for 2–6 days, we analyzed endogenous mouse (m)PTHrP gene expression (by real-time PCR) (a); PTHrP protein (by western blot, using antibody C6 recognizing both endogenous PTHrP and the human PTHrP transgene) (b); and the PTH1R gene (by real-time PCR) and protein (by western blot) expression (a, b). Representative autoradiograms are also shown in (b). Experimental values are mean±s.e.m. of 4–6 mice per group at each time period. All values were normalized against corresponding sham control. *P<0.01 vs corresponding value in control mice; aP<0.01 vs corresponding value in sham-operated mice. AU, arbitrary units. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 2 Evolution of renal lesions, as well as inflammatory cell infiltration, up to 6 days in the obstructed kidney of control and PTHrP-TG mice. Renal lesions (assessed by Masson's staining, original magnification × 100) (a), the number of renal interstitial macrophages (determined by F4/80 staining) (b), and T lymphocytes (identified by CD3 positivity) (c) (original magnification × 200) in the kidney of representative control and PTHrP-TG mice at the indicated days of obstruction or sham operation are shown. Score values are mean±s.e.m. of 4–6 animals per group at each time. These values corresponding to sham-operated and contralateral kidneys were unchanged throughout the period of study, and thus those for the different times in each group were pooled. *P<0.01 vs corresponding value in control mice. aP<0.01 vs corresponding value in sham-operated mice. ND, not detected. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 3 Changes in several proinflammatory factors in the obstructed kidney of control and PTHrP-TG mice. Protein expression of MCP-1 (a) (representative autoradiogram of western blot analysis is shown) and gene expression of CCR2 (b) RANTES (c), ICAM-1 (d), and IL-6 (e) (determined by real time PCR) in the kidney of both types of mice at 2–6 days after UUO or sham operation. Experimental values are mean±s.e.m. of 4–6 animals per group at each time. *P<001 vs corresponding value in control mice. aP<0.01 vs corresponding value in sham-operated mice. AU, arbitrary units. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 4 Changes in NFκB activation in the obstructed mouse kidney. NF-κB activation was determined by EMSA in total kidney extracts from PTHrP-TG and control mice at day 4 after UUO or sham operation, as described in the text. Some PTHrP-TG mice were pretreated with doxycycline (doxy) (20 mg l−1 in the drinking water) for 1 week before and during obstruction (4 days) to suppress PTHrP overexpression. A representative EMSA is shown (upper panel). As control for specificity, cell extracts were pre-incubated with a 100-fold excess of unlabeled NF-κB oligonucleotide for 10 min at 4 °C before adding the labeled probe. Relative densitometric values as mean±s.e.m. over that of sham-operated control from four animals per group are shown (lower panel). aP<0.01 vs corresponding sham or contralateral kidney values. *P<0.01 vs corresponding control and doxy-treated values. AU, arbitrary units. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 5 Effect of doxycyclin on several proinflammatory factors in the obstructed kidney of PTHrP-TG mice. Treatment with doxycycline, as described in the legend to Figure 4, reduced CCR2 (a), RANTES (b), and ICAM-1 (c) gene upregulation (by real-time PCR) in PTHrP-TG mice to the corresponding levels in control mice at day 4 after UUO. Experimental values are mean±s.e.m. of 4–6 animals per group at each time. *P<0.01 vs corresponding value in control mice; aP<0.01 vs corresponding value in sham-operated mice; bP<0.01 vs corresponding PTHrP-TG value. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 6 Effect of a PTH1R antagonist on various proinflammatory alterations in the obstructed kidney of control mice. The number of renal interstitial macrophages (identified by F4/80 staining) and T lymphocytes (assessed by CD3 positivity) (a), as well as MCP-1 protein expression (representative autoradiogram of western blot analysis is shown) and RANTES mRNA expression (by real-time PCR) (b) were evaluated in the kidney of control mice at day 4 after UUO or sham operation. PTHrP (7–34) was administered to a group of mice at 35 μg per animal per day, 1 day before and during obstruction for 4 days. Experimental values are mean±s.e.m. of at least four animals per group. aP<0.01 vs value in sham-operated mice. *P<0.01; **P<0.05 vs value in untreated mice. AU, arbitrary units. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 7 Effect of Ang II antagonists on both PTHrP expression and proinflammatory alterations in the obstructed mouse kidney. (a) Mouse (m)PTHrP gene expression was analyzed by real-time PCR in the kidney of control mice at day 2 after UUO or sham operation. The number of renal interstitial macrophages (identified by F4/80 positivity) (b) and MCP-1 protein expression (shown a representative autoradiogram of western blot analysis) (c) were evaluated in the kidney of either PTHrP-TG mice or their control littermates at day 4 after UUO or sham operation. Losartan and PD123319 (10 and 30 mg kg−1 day−1, respectively) were treated intraperitoneally 1 day before and also daily following UUO for the period studied in each case. Experimental values are mean±s.e.m. of 4–6 animals per group. aP<0.01 vs corresponding value in sham-operated mice. *P<0.01 vs corresponding value in untreated mice. AU, arbitrary units. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 8 PTHrP (1–36) induces NF-κB and ERK activation in tubuloepithelial MCT cells. (a) PTHrP (1–36), at 100 nM, induced NF-κB–DNA binding (analyzed by electrophoretic mobility shift assay (EMSA)) with a maximum at 20–30 min. Pretreatment with U0126 (25 μM) significantly reduced this effect of PTHrP (1–36), without affecting basal NF-κB activity (data not shown), in these cells. To characterize the proteins of NF-κB–DNA complex, in some experiments, nuclear extracts from MCT cells after stimulation with PTHrP (1–36) for 30 min were pre-incubated with an anti-p50 or anti-p65 antibody. As control for specificity of the binding reaction, these nuclear extracts were pre-incubated with a 100-fold excess of unlabeled NF-κB oligonucleotide. Densitometric values are mean±s.e.m. from three independent experiments in duplicate. (b) PTHrP (1–36), at 100 nM, induced ERK phosphorylation in MCT cells. Western blot analysis was performed in MCT cell extracts using antibodies against pERK 1/2 or ERK 1/2. Basal=nonstimulated control (at 5 min). Relative densitometric values corresponding to pERK/ERK changes are mean±s.e.m. from three independent measurements in duplicate. Representative autoradiograms for EMSA (a) and immunoblot analysis (b) are shown. *P<0.01 vs corresponding basal value (100%) and U0126-treated value. aP<0.01 vs corresponding PTHrP (1–36)-treated value at 30 min. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 9 PTHrP (1–36) induces p65 protein accumulation into the nucleus in MCT cells. Serum-depleted cells grown on multiwell chambers were untreated (basal) or treated with PTHrP (1–36) (100 nM) for different time periods (a) or with PTHrP (1–36) at different doses for 30 min (b). Double immunofluorescence staining was assessed, for the nucleus (with propidium iodide (IP); red) and using a fluorescein isothiocyanate-labeled IgG (green) for p65 detection. The overlaid images in red and green (merge) yielded an orange tone in the cell nucleus denoting the presence of intense nuclear p65 fluorescence in PTHrP (1–36)-treated MCT cells for 30 min. Pretreatment with the ERK inhibitor U0126 (25 μM) abolished this effect of PTHrP (1–36) (a). This represents the results of three independent experiments. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 10 PTHrP (1–36) time and dose dependently increases MCP-1 and RANTES gene expression in MCT cells. MCP-1 (a) and RANTES (b) mRNA levels were evaluated by real-time PCR. In some experiments, cells were pre-treated with PTHrP (7–34) (1 μM) for 1 h before addition of PTHrP (1–36) (100 nM) (a and b, left). Experimental values are mean±s.e.m. from three independent experiments in duplicate. *P<0.01; **P<0.05 vs basal value. aP<0.01; bP<005 vs corresponding value at 10 nM PTHrP (1–36). Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 11 Effect of different inhibitors on upregulation of proinflammatory factors induced by PTHrP (1–36) in MCT cells. Cells were treated with PTHrP (1–36) (100 nM) for 1 h. MCP-1 (a), RANTES (b), as well as IL-6 and CCR2 (c) mRNA levels were evaluated by real-time PCR. Different NF-κB inhibitors, MG-132 (10 μM), Bay 11-7082 (25 μM), and parthenolide (25 μM), the ERK inhibitor U0126 (25 μM), or PTHrP (7–34) (1 μM) were added 1 h before addition of the PTHrP peptide. Experimental values are mean±s.e.m. from three independent experiments in duplicate. aP<0.01 vs basal value. *P<0.01 vs PTHrP (1–36) alone value. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions

Figure 12 PTHrP (1–36) induces migration of Raw 264.7 cells in vitro. (a) Serum-depleted MCT cells were exposed or not (basal) to PTHrP (1–36) (100 nM) with or without different inhibitors for 12 h. The resulting PTHrP (1–36)-treated or untreated cell-conditioned medium (PT-CM or PU-CM, respectively) was tested for chemoattractant activity on Raw 264.7 cells as described in the text. PTHrP (7–34) was used at 1 μM, and NF-κB inhibitors and U0126 were used at the same concentrations as in Figure 11. Addition of PTHrP (7–34) (1 μM) or neutralizing N-terminal anti-PTHrP antiserum C13, but not C-terminal anti-PTHrP antiserum C6 or pre-immune rabbit serum (data not shown), or an MCP-1 antibody (each at 1:100) to PT-CM significantly reduced Raw 264.7 cells' migration. Direct treatment of Raw 264.7 cells with PTHrP (1–36) (100 nM) stimulated these cells' migration (b) and MCP-1 gene expression (c); and both effects were inhibited by PTHrP (7–34). Moreover, the former effect was also abolished by an MCP-1 antibody. Experimental values are mean±s.e.m. from at least three independent experiments in duplicate. aP<0.01 vs basal medium value. bP<0.01 vs PT-CM alone (-) value. *P<0.01 vs PU-CM values, with or without (-) inhibitors. #P<0.01 vs basal value and values corresponding to PTHrP (1–36) at <10−8 M or in the presence of different inhibitors. Kidney International 2008 73, 835-847DOI: (10.1038/sj.ki.5002775) Copyright © 2008 International Society of Nephrology Terms and Conditions