scholarly journals Temporal analysis of signaling pathways activated in a murine model of two-kidney, one-clip hypertension

2009 ◽  
Vol 297 (4) ◽  
pp. F1055-F1068 ◽  
Author(s):  
Jingfei Cheng ◽  
Wei Zhou ◽  
Gina M. Warner ◽  
Bruce E. Knudsen ◽  
Vesna D. Garovic ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Murine Model ◽  
Proliferative Response ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Nuclear Antigen ◽  
Tubular Atrophy ◽  
Ki 67 ◽  
P53 Expression ◽  
Contralateral Kidney

Unilateral renal artery stenosis (RAS) leads to atrophy of the stenotic kidney and compensatory enlargement of the contralateral kidney. Although the two-kidney, one-clip (2K1C) model has been extensively used to model human RAS, the cellular responses in the stenotic and contralateral kidneys, particularly in the murine model, have received relatively little attention. We studied mice 2, 5, and 11 wk after unilateral RAS. These mice became hypertensive within 1 wk. The contralateral kidney increased in size within 2 wk after surgery. This enlargement was associated with a transient increase in expression of phospho-extracellular signal-regulated kinase (p-ERK), the proliferation markers proliferating cell nuclear antigen and Ki-67, the cell cycle inhibitors p21 and p27, and transforming growth factor-β, with return to baseline levels by 11 wk. The size of the stenotic kidney was unchanged at 2 wk but progressively decreased between 5 and 11 wk. Unlike the contralateral kidney, which showed minimal histopathological alterations, the stenotic kidney developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Surprisingly, the stenotic kidney showed a proliferative response, which involved largely tubular epithelial cells. The atrophic kidney had little evidence of apoptosis, despite persistent upregulation of p53; expression of cell cycle regulatory proteins in the stenotic kidney was persistently increased through 11 wk. These studies indicate that in the 2K1C model, the stenotic kidney and contralateral, enlarged kidney exhibit a distinct temporal expression of proteins involved in cell growth, cell survival, apoptosis, inflammation, and fibrosis. Notably, an unexpected proliferative response occurs in the stenotic kidney that undergoes atrophy.

scholarly journals Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension

2012 ◽  
Vol 302 (11) ◽  
pp. F1455-F1464 ◽  
Author(s):  
Gina M. Warner ◽  
Jingfei Cheng ◽  
Bruce E. Knudsen ◽  
Catherine E. Gray ◽  
Ansgar Deibel ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Artery ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Plasma Renin ◽  
Tubular Atrophy ◽  
Similar Reduction ◽  
Exon 2 ◽  
Contralateral Kidney ◽  
Interstitial Inflammation

Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

An Immunostaining Panel for Diagnosis of Malignancy in Mucinous Tumors of the Pancreas

2001 ◽  
Vol 125 (6) ◽  
pp. 765-769
Author(s):  
Jin Zhao ◽  
Sharon X. Liang ◽  
Lou Savas ◽  
Barbara F. Banner
Keyword(s):  
Chronic Pancreatitis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Pancreatic Tissue ◽  
Malignant Potential ◽  
Ki 67 ◽  
P53 Expression ◽  
Normal Pancreatic Tissue ◽  
Cystic Tumors ◽  
Her 2

Abstract Background.—The diagnosis of malignancy in pancreatic mucinous cystic tumors depends on demonstrating invasion that may be focal and require extensive sectioning. Objective.—To explore markers that may indicate malignant potential in mucinous cystic tumors. Design.—Routinely processed sections from resected specimens of 12 normal pancreata, 14 pancreata with chronic pancreatitis, 9 mucinous cystic tumors, and 30 invasive adenocarcinomas were immunostained with antibodies to p53, HER-2/neu, epithelial growth factor receptor (EGFR), transforming growth factor α (TGF-α), and Ki-67. Results.—Expression of p53, HER-2/neu, and Ki-67 was significantly more frequent in mucinous tumors than in normal pancreatic tissue and chronic pancreatitis tissue (P = .0003 to .05). Strong expression (more than one third of cells positive) and strong intensity (2+ and 3+) of staining of p53 and EGFR were seen only in carcinomas. Coexpression of p53/HER-2/neu and EGFR/HER-2/neu and a frequency of Ki-67+ nuclei of greater than 5% of cells discriminated between mucinous tumors and normal pancreatic tissue and chronic pancreatitis tissue. p53 expression was significantly more frequent in carcinomas than in mucinous tumor (P = .0326). Coexpression of p53/EGFR discriminated between mucinous tumors and carcinomas; however, TGF-α was not discriminative. Conclusions.—The immunostaining panel of p53, HER-2/neu, Ki-67, and EGFR can be helpful in indicating malignant potential in mucinous tumors of pancreas in routine pathology practice.

The cell cycle associated change of the Ki-67 reactive nuclear antigen expression

1987 ◽  
Vol 133 (3) ◽  
pp. 579-584 ◽  
Author(s):  
Kohsuke Sasaki ◽  
Tomoyuki Murakami ◽  
Masahiro Kawasaki ◽  
Manabu Takahashi
Keyword(s):  
Cell Cycle ◽  
Antigen Expression ◽  
Nuclear Antigen ◽  
Ki 67

Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value

1997 ◽  
Vol 86 (1) ◽  
pp. 121-130 ◽  
Author(s):  
Julie M. Cunningham ◽  
David W. Kimmel ◽  
Bernd W. Scheithauer ◽  
Judith R. O'Fallon ◽  
Paul J. Novotny
Keyword(s):  
Univariate Analysis ◽  
Tumor Grade ◽  
Nuclear Antigen ◽  
Clinicopathological Parameters ◽  
Proliferative Potential ◽  
Ki 67 ◽  
Proliferation Markers ◽  
P53 Expression ◽  
Content Type ◽  
Mib 1

✓ Consecutive paraffin sections of 105 astrocytomas and 15 oligoastrocytomas were examined for expression of p53, MIB-1 (Ki-67), and proliferating cell nuclear antigen (PCNA). The tumors had been examined previously for genetic abnormalities and by flow cytometry. Regardless of the tumor's stage and grade and the patient's age and gender, p53 expression was found in 40% of tumors. Although p53 expression was associated with a loss on chromosome 17p and was more frequent in aneuploid tumors, it had no association with survival time. The MIB-1 and PCNA labeling indices increased with increasing tumor grade but showed no association with other clinicopathological parameters. In individual tumors, there was poor concordance between any of the variables (MIB-1, PCNA, and p53). Results for p53 and MIB-1 were similar for both astrocytomas and oligoastrocytomas. The MIB-1 and PCNA values appeared to have prognostic utility in univariate analysis but not after adjusting for patient age and tumor grade. The poor concordance between MIB-1 and PCNA in individual tumors indicates that any one means of assessing proliferative potential in gliomas may not be reliable.

scholarly journals Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle

2006 ◽  
Vol 174 (5) ◽  
pp. 625-630 ◽  
Author(s):  
Vlastimil Srsen ◽  
Nicole Gnadt ◽  
Alexander Dammermann ◽  
Andreas Merdes
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
S Phase ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
Mitogen Activated Protein ◽  
Centrosome Proteins ◽  
Centrosome Protein

Previous evidence has indicated that an intact centrosome is essential for cell cycle progress and that elimination of the centrosome or depletion of individual centrosome proteins prevents the entry into S phase. To investigate the molecular mechanisms of centrosome-dependent cell cycle progress, we performed RNA silencing experiments of two centrosome-associated proteins, pericentriolar material 1 (PCM-1) and pericentrin, in primary human fibroblasts. We found that cells depleted of PCM-1 or pericentrin show lower levels of markers for S phase and cell proliferation, including cyclin A, Ki-67, proliferating cell nuclear antigen, minichromosome maintenance deficient 3, and phosphorylated retinoblastoma protein. Also, the percentage of cells undergoing DNA replication was reduced by &gt;50%. At the same time, levels of p53 and p21 increased in these cells, and cells were predisposed to undergo senescence. Conversely, depletion of centrosome proteins in cells lacking p53 did not cause any cell cycle arrest. Inhibition of p38 mitogen-activated protein kinase rescued cell cycle activity after centrosome protein depletion, indicating that p53 is activated by the p38 stress pathway.

Klotho overexpression protects against renal aging along with suppressions of transforming growth factor-β1 signaling pathways

2021 ◽  
Author(s):  
Hiroaki Oishi ◽  
Shigehiro Doi ◽  
Ayumu Nakashima ◽  
Takeshi Ike ◽  
Yujiro Maeoka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Inhibitory Effect ◽  
Signaling Molecules ◽  
Serum Phosphate Level ◽  
Old Mice

Klotho is an anti-aging protein reported to suppress transforming growth factor (TGF)-b1 signaling. Aging kidneys are characterized by interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress. TGF-b1 signaling is involved in these processes. In this study, we investigated whether klotho overexpression improves these features in the kidneys of aging mice, and examined the inhibitory effect of klotho on signaling molecules related to transforming growth of TGF-b1. Klotho transgenic (KLTG) and wild type (WT) mice were used, and 8-week-old and 24-month-old mice were defined as young and aging, respectively. We found that klotho expression was decreased in aging WT mice, but it was maintained in aging KLTG mice. Klotho overexpression improved the survival of 24-month-old mice. Although the serum calcium level was significantly lower in aging KLTG mice than in aging WT mice, the serum phosphate level did not differ between these mice. Klotho overexpression attenuated the increases in blood pressure, serum blood urea nitrogen level, and serum creatinine level in aging mice. Interstitial fibrosis, accumulation of cell cycle-arrested cells, and oxidative stress did not differ between young KLTG and WT mice, but they were significantly suppressed in aging KLTG mice compared with aging WT mice. Furthermore, the expression of TGF-b1-related signaling molecules was increased in aging WT mice, whereas it was inhibited in aging KLTG mice. These data suggest that klotho overexpression protects against kidney aging along with suppression of TGF-b1 signaling pathways.

scholarly journals Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

2014 ◽  
Vol 307 (4) ◽  
pp. F471-F484 ◽  
Author(s):  
Florin L. Craciun ◽  
Amrendra K. Ajay ◽  
Dana Hoffmann ◽  
Janani Saikumar ◽  
Steven L. Fabian ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Wild Type ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Surface Receptors ◽  
Fibrotic Disorders ◽  
Vehicle Treated Control

Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (∼75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.

Prognostic factors in bladder carcinoma: Histologic parameters and expression of a cell cycle-related nuclear antigen (Ki-67)

1992 ◽  
Vol 166 (1) ◽  
pp. 37-43 ◽  
Author(s):  
A. H. Mulder ◽  
J. C. S. P. Van Hootegem ◽  
R. Sylvester ◽  
F. J. W. Ten Kate ◽  
K. H. Kurth ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Prognostic Factors ◽  
Bladder Carcinoma ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
A Cell

Ki-67 Labeling Index in Breast Cancer

1989 ◽  
Vol 75 (6) ◽  
pp. 557-562 ◽  
Author(s):  
Sergio Crispino ◽  
Ambrogio Brenna ◽  
Daniela Colombo ◽  
Bajardo Flores ◽  
Silvestro D'Amico ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Monoclonal Antibody ◽  
Menopausal Status ◽  
Mitotic Rate ◽  
Labeling Index ◽  
Nuclear Antigen ◽  
Proliferating Cells ◽  
Cell Cycle Kinetics ◽  
Ki 67

Measurements of cell cycle kinetics have been found to correlate with the clinical course of patients with breast cancer. However, the thymidine labeling index and more rapid methods like flow cytometry remain complicated and costly. We assessed cell proliferation of 67 breast carcinomas by an immunoperoxidase procedure using a monoclonal antibody, Ki-67, which reacts with a nuclear antigen in proliferating cells. The percentage of Ki-67 positive cells ranged from 2% to 70 %. Tumors with high mitotic rate, high nuclear grade, high histologic grade, and negative estrogen receptors had statistically higher Ki-67 labeling rates. We found no significant differences between the Ki-67 labeling rate and other clinical (age at diagnosis, menopausal status) or pathologic (necrosis, fibrosis, vascular invasion, lymphatic invasion, cellular reaction, tumor size, lymph node metastases) features assessed. These results parallel previously reported data, and confirm that this immunohistochemical staining of breast carcinoma by Ki-67 monoclonal antibody can be considered a rapid and convenient method for assessing cell cycle kinetics. However, further studies, evaluating the correlation between Ki-67 labeling rate and prognosis are needed to better define the real usefulness of this analysis in clinical practice.

ACE inhibition increases expression of the ETBreceptor in kidneys of mice with unilateral obstruction

2003 ◽  
Vol 284 (1) ◽  
pp. F209-F217 ◽  
Author(s):  
Kazuaki Moridaira ◽  
Jeremiah Morrissey ◽  
Melanie Fitzgerald ◽  
Guangjie Guo ◽  
Ruth McCracken ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Enzyme Inhibitor ◽  
Interstitial Fibrosis ◽  
Kidney Cortex ◽  
Collagen Type Iv ◽  
Contralateral Kidney ◽  
Interstitial Volume ◽  
Endothelin A ◽  
Enalapril Treatment

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive peptide, may play an important role in some types of renal disease. To investigate the effects of angiotensin II on endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without enalapril, an orally active angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of endothelin-1, endothelin A, and endothelin B (ETB) along with transforming growth factor-β, TNF-α, and collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that enalapril administration ameliorated the increased expression of ET-1 mRNA in the obstructed kidney by 44% ( P < 0.02). Although the level of endothelin A mRNA expression was significantly increased in the obstructed kidney, it was not affected by enalapril. We found that enalapril treatment increased ETB mRNA expression by 115% ( P < 0.05) and protein expression (measured by Western blot) in the kidney with an obstructed ureter. Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with enalapril and the ETB receptor antagonist BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that enalapril inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of enalapril on the obstructed kidney by potentially stimulating the production of nitric oxide through an increased expression of the ETB receptor.

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