Proteinuria and glomerulosclerosis in the Sabra genetic rat model of salt susceptibility

2002 ◽  
Vol 9 (3) ◽  
pp. 167-178 ◽  
Author(s):  
Chana Yagil ◽  
Marina Sapojnikov ◽  
Gurion Katni ◽  
Zvi Ilan ◽  
Sarah Weksler Zangen ◽  
...  
Keyword(s):  
Rat Model ◽  
Chromosome 17 ◽  
Chromosome 1 ◽  
Salt Loading ◽  
Protein Excretion ◽  
Histopathological Evaluation ◽  
Rat Strain ◽  
Salt Susceptible ◽  
Grade 3

In search of an experimental model that would simulate the association between proteinuria and salt sensitivity in humans, we studied protein excretion in the Sabra rat model of salt susceptibility. Monthly measurements of urinary protein excretion in animals fed standard rat chow revealed that normotensive salt-sensitive SBH/y developed proteinuria that averaged 65 ± 7 mg/day ( n = 10) at 9 mo, whereas proteinuria in normotensive salt-resistant SBN/y was 39 ± 4 mg/day ( n = 10) ( P < 0.01). Histopathological evaluation revealed focal and segmental glomerulosclerosis (FSGS) lesions grade 2 in SBH/y and normal histology in SBN/y. To amplify the differences between the strains, uninephrectomy was performed. At 9 mo, proteinuria in SBH/y with one kidney (SBH/y-1K) was 195 ± 12 mg/day ( n = 10) and in SBN/y was 128 ± 10 mg/day ( n = 10) ( P < 0.001); histopathology revealed FSGS grade 3 in SBH/y-1K and grade 1–2 in SBN/y-1K. To determine the effect of salt loading, animals were provided with 8% NaCl in chow, causing hypertension in SBH/y but not in SBN/y. Proteinuria markedly increased in both SBH/y with two kidneys (SBH/y-2K) and SBH/y-1K, but not in SBN/y; histopathology revealed FSGS grade 1–2 in SBH/y-2K, grade 2 in SBH/y-1K, no lesions in SBN/y-2K, and grade 0–1 in SBN/y-1K. We concluded that the SBH/y strain is more susceptible to develop proteinuria and glomerulosclerosis than SBN/y. In search for the genetic basis of this phenomenon, we investigated the role of candidate proteinuric gene loci. Consomic strains were constructed by introgressing chromosome 1 (which harbors the rf-1 and rf-2 proteinuric loci) or chromosome 17 (which harbors rf-5) from SBH/y onto the SBN/y genomic background. The resulting consomic strains developed marked proteinuria that was severalfold higher than in SBN/y-1K; histopathological evaluation, however, revealed FSGS lesions grade 1–2, similar to those found in SBN/y-1K and less severe than in SBH/y-1K. These results suggest a functional role of gene systems located on chromosomes 1 and 17 in inducing proteinuria in the salt-susceptible Sabra rat strain. These genetic loci do not appear to harbor major genes for glomerulosclerosis.

Congenic strains confirm the presence of salt-sensitivity QTLs on chromosome 1 in the Sabra rat model of hypertension

2003 ◽  
Vol 12 (2) ◽  
pp. 85-95 ◽  
Author(s):  
Chana Yagil ◽  
Norbert Hubner ◽  
Reinhold Kreutz ◽  
Detlev Ganten ◽  
Yoram Yagil
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Response ◽  
Significant Rise ◽  
Pressure Response ◽  
Chromosome 1 ◽  
Unexpected Finding ◽  
Salt Loading ◽  
Congenic Strains ◽  
Tail Cuff

We previously detected by linkage analysis in segregating populations derived from crosses between the Sabra hypertension-prone rat (SBH/y) and the hypertension-resistant strain (SBN/y) two QTLs for salt susceptibility on chromosome 1, with sex specificity: in males SS1a and SS1b, and in females SS1b only. To provide support for a functional role of these QTLs in relation to hypertension, we constructed congenic strains by replacing most of or selected segments from chromosome 1 from SBN/y with the homologous chromosomal regions of SBH/y, or reciprocally from SBH/y with segments of SBN/y, leaving the other chromosomes unperturbed. Genetic screening with over 150 microsatellite markers confirmed the homozygosity of the targeted genomic inserts and of the remainder of the genomic background. The phenotype of the congenic strains was tested by salt loading with DOCA-salt over a 4-wk period and measuring blood pressure by tail-cuff (in all animals) or radiotelemetry (in select groups) at baseline and during salt loading. In the congenic strains in which a chromosomal segment incorporating QTL SS1a from SBN/y was introgressed onto the genomic background of SBH/y, the blood pressure response to salt loading, as measured by tail-cuff, was decreased by 16 mmHg in both males and females compared with the parental SBH/y; replacing the QTL SS1b reduced the blood pressure response by 30 and 21 mmHg, respectively. In the congenic strains in which both SS1a and SS1b were introgressed from SBN/y onto the genomic background of SBH/y, the reduction in blood pressure was 34 mmHg in males and 38 mmHg in females; these latter results were confirmed by radiotelemetry. When either one or both QTLs together were introgressed from SBH/y onto the SBN/y genomic background, tail-cuff measurements failed to detect an increase in blood pressure above baseline; telemetric measurements in the congenic strains introgressing both QTLs together, however, detected a significant rise in blood pressure after 3 and 4 wk of salt loading. Neither the origin of the Y chromosome nor the sex of the parental strain had any significant impact on the magnitude of the blood pressure response to salt loading. We conclude that the congenic rat strains that we constructed for the chromosome 1 QTLs provide functional evidence for the role of gene systems within QTLs SS1a and SS1b in the blood pressure response to salt loading. The unexpected finding was that QTL SS1a contributes to the hypertensive response also in females. The data indicate the lack of a Y chromosomal effect or of parental imprinting.

POSSIBLE ROLE OF 5α-ANDROSTANE-3α,17β-DIOL IN THE CONTROL OF FOLLICLE-STIMULATING HORMONE SECRETION IN THE IMMATURE FEMALE RAT

1982 ◽  
Vol 92 (1) ◽  
pp. 37-42 ◽  
Author(s):  
H. M. A. MEIJS-ROELOFS ◽  
P. KRAMER ◽  
L. GRIBLING-HEGGE
Keyword(s):  
Inhibitory Action ◽  
Combined Treatment ◽  
Hormone Secretion ◽  
Inhibitory Effect ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Immature Rat ◽  
Rat Strain ◽  
Intact Rats

A possible role of 5α-androstane-3α,17β-diol (3α-androstanediol) in the control of FSH secretion was studied at various ages in ovariectomized rats. In the rat strain used, vaginal opening, coincident with first ovulation, generally occurs between 37 and 42 days of age. If 3α-androstanediol alone was given as an ovarian substitute, an inhibitory effect on FSH release was evident with all three doses tested (50, 100, 300 μg/100 g body wt) between 13 and 30 days of age; at 33–35 days of age only the 300 μg dose caused some inhibition of FSH release. Results were more complex if 3α-androstanediol was given in combined treatment with oestradiol and progesterone. Given with progesterone, 3α-androstanediol showed a synergistic inhibitory action on FSH release between 20 and 30 days of age. However, when 3α-androstanediol was combined with oestradiol a clear decrease in effect, as compared to the effect of oestradiol alone, was found between 20 and 30 days of age. Also the effect of combined oestradiol and progesterone treatment was greater than the effect of combined treatment with oestradiol, progesterone and 3α-androstanediol. At all ages after day 20 none of the steroid combinations tested was capable of maintaining FSH levels in ovariectomized rats similar to those in intact rats. It is concluded that 3α-androstanediol might play a role in the control of FSH secretion in the immature rat, but after day 20 the potentially inhibitory action of 3α-androstanediol on FSH secretion is limited in the presence of oestradiol.

scholarly journals New homozygous gpt delta transgenic rat strain improves an efficiency of the in vivo mutagenicity assay

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Kenichi Masumura ◽  
Tomoko Ando ◽  
Akiko Ukai ◽  
Sho Fujiwara ◽  
Shigeo Yokose ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Gene Mutation ◽  
Point Mutations ◽  
Chromosome 1 ◽  
Transgenic Rat ◽  
Target Tissue ◽  
Sequencing Analysis ◽  
Rat Strain ◽  
Packaging Efficiency

Abstract Background Gene mutation assays in transgenic rodents are useful tools to investigate in vivo mutagenicity in a target tissue. Using a lambda EG10 transgene containing reporter genes, gpt delta transgenic mice and rats have been developed to detect point mutations and deletions. The transgene is integrated in the genome and can be rescued through an in vitro packaging reaction. However, the packaging efficiency is lower in gpt delta rats than in mice, because of the transgene in gpt delta rats being heterozygous and in low copy number. To improve the packaging efficiency, we herein describe a newly developed homozygous gpt delta rat strain. Results The new gpt delta rat has a Wistar Hannover background and has been successfully maintained as homozygous for the transgene. The packaging efficiency in the liver was 4 to 8 times higher than that of existing heterozygous F344 gpt delta rats. The frequency of gpt point mutations significantly increased in the liver and bone marrow of N-nitroso-N-ethylurea (ENU)- and benzo[a]pyrene (BaP)-treated rats. Spi− deletion frequencies significantly increased in the liver and bone marrow of BaP-treated rats but not in ENU-treated rats. Whole genome sequencing analysis identified ≥ 30 copies of lambda EG10 transgenes integrated in rat chromosome 1. Conclusions The new homozygous gpt delta rat strain showed a higher packaging efficiency, and could be useful for in vivo gene mutation assays in rats.

scholarly journals WEE1 Inhibitor: Clinical Development

2021 ◽  
Vol 23 (9) ◽  
Author(s):  
Anthony Kong ◽  
Hisham Mehanna
Keyword(s):  
Clinical Trials ◽  
Tp53 Mutation ◽  
Predictive Biomarker ◽  
Concurrent Chemotherapy ◽  
Clinical Development ◽  
Novel Agents ◽  
The Novel ◽  
Grade 3 ◽  
Chemotherapy Agents

Abstract Purpose of Review WEE1 inhibitor has been shown to potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly in p53-mutated or deficient cancer cells although not exclusively. Here, we review the clinical development of WEE1 inhibitor in combination with chemotherapy or radiotherapy with concurrent chemotherapy as well as its combination with different novel agents. Recent Findings Although several clinical trials have shown that WEE1 inhibitor can be safely combined with different chemotherapy agents as well as radiotherapy with concurrent chemotherapy, its clinical development has been hampered by the higher rate of grade 3 toxicities when added to standard treatments. A few clinical trials had also been conducted to test WEE1 inhibitor using TP53 mutation as a predictive biomarker. However, TP53 mutation has not been shown to be the most reliable predictive biomarker and the benefit of adding WEE1 inhibitor to chemotherapy has been modest, even in TP53 biomarker-driven studies. Summary There are ongoing clinical trials testing WEE1 inhibitor with novel agents such as ATR and PAPR inhibitors as well as anti-PDL1 immunotherapy, which may better define the role of WEE1 inhibitor in the future if any of the novel treatment combination will show superior anti-tumor efficacy with a good safety profile compared to monotherapy and/or standard treatment.

The role of exudation in chronic subdural hematomas

2007 ◽  
Vol 107 (2) ◽  
pp. 290-295 ◽  
Author(s):  
Mehmet Tokmak ◽  
A. Celal Iplikcioglu ◽  
Sirzat Bek ◽  
Cem Atilla Gökduman ◽  
Mustafa Erdal
Keyword(s):  
Outer Membrane ◽  
Clinical Status ◽  
Ct Scans ◽  
Subdural Hematomas ◽  
The Mean ◽  
Grade 3 ◽  
Age Range ◽  
Exudation Rate

Object Chronic subdural hematomas (SDHs) are a local inflammatory process that causes the formation of a granulation tissue often referred to as the external or outer membrane. This membrane has abnormally permeable macrocapillaries. Therefore, exudation from the macrocapillaries in the outer membrane of chronic SDH may play an important role in the enlargement of chronic SDH. In this study the authors investigated the role of exudation in chronic SDH. Methods The authors examined 24 patients (16 men and eight women; age range 38–86 years [mean age 61.4 years]) with 27 chronic SDHs. The clinical status of the patients was evaluated according to the classification described by Markwalder. The diagnosis was established on computed tomography (CT) scans in all cases. The authors also used the Nomura Classification for judging the lesion's appearance on CT scans. Immediately after the diagnosis, all patients were administered 20 mCi (740 mBq) technetium-99m human serum albumin. Four hours later, blood and SDH samples were taken and radioactivity levels were measured in each. The ratio of activity of the samples taken from chronic SDH to the radioactivity of blood was determined as a percentage and defined as the exudation rate. On the follow-up CT scan obtained on postoperative Day 20, subdural collections thicker than 5 mm were determined to be a reaccumulation. Results The correlations between the exudation rate and age of the patients, clinical grades, CT appearances, and amount of reaccumulation were investigated. In this series the average exudation rate was 13.24% (range 2.05–28.88%). The mean exudation rates according to the clinical grades assigned to patients were as follows: Grade 0, 8.67 ± 5.64% (three patients); Grade 1, 5.07 ± 1.43% (eight patients); Grade 2, 17.87 ± 3.73% (seven patients); and Grade 3, 19.65 ± 7.67% (six patients). Exudation rates in patients with Grades 2 and 3 were significantly higher than those in Grades 0 and 1 (p < 0.05). The mean exudation rates according to the lesion's appearance on CT scans were found as follows: hypodense appearance, 6.55 ± 4.52% (eight patients); isodense appearance, 11.07 ± 6.32% (five patients); hyperdense appearance, 19.47 ± 13.61% (three patients); and mixed-density appearance, 17.40 ± 5.80% (nine patients). The differences among the groups were significant (p < 0.05). The average exudation rate was statistically higher in the patients with reaccumulation (16.30 ± 8.16%) than that in the patients without reaccumulation (9.96 ± 6.84%) (p < 0.05). Conclusions The exudation rate in chronic SDH is correlated with a higher clinical grade (Markwalder Grade 2 or 3), mixed-density CT appearance, and reaccumulation. Therefore, exudation from macrocapillaries in the outer membrane of chronic SDH probably plays an important role in the pathophysiology and the growth of chronic SDH.

scholarly journals PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression

2021 ◽  
Author(s):  
Jonathan Weller ◽  
Sophie Katzendobler ◽  
Philipp Karschnia ◽  
Stefanie Lietke ◽  
Rupert Egensperger ◽  
...  
Keyword(s):  
Stereotactic Biopsy ◽  
Tumor Volume ◽  
Progression Free Survival ◽  
Who Grade ◽  
Free Survival ◽  
First Relapse ◽  
Pcv Chemotherapy ◽  
Grade 3 ◽  
Histological Progression

Abstract Introduction The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. Methods Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. Results PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. Conclusions PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.

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