scholarly journals Spontaneous Age-Related Histopathological Changes in Microminipigs

2019 ◽  
Vol 47 (7) ◽  
pp. 817-832 ◽  
Author(s):  
Akihisa Kangawa ◽  
Toshiaki Nishimura ◽  
Takashi Nishimura ◽  
Masayoshi Otake ◽  
Satoko Enya ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Uterine Leiomyoma ◽  
Interstitial Fibrosis ◽  
Renal Medulla ◽  
Histopathological Changes ◽  
Follicular Cells ◽  
Thymic Involution ◽  
Renal Interstitial Fibrosis ◽  
Intimal Proliferation ◽  
Age Related

Microminipigs have become an attractive animal model for toxicology and pharmacology studies and for human disease models, owing to their manageable size. Although there are numerous reports of spontaneous age-related lesions in mice, rats, dogs, and monkeys, those in minipigs are scarce. In the present study, spontaneous age-related histopathological changes were investigated using 37 microminipigs (20 males and 17 females) that were 6 months to 10 years of age. Abnormal deposits of materials were evident in several animals from 6 years of age, and these deposits included amyloid in the renal medulla, thyroid gland, and adrenal gland, hyaline droplets in glomeruli, and fibrillar inclusions in neurons. Arterial sclerosing changes (intimal thickening, intimal proliferation, and medial mineralization) and proliferative lesions (hyperplasia of hepatocytes, follicular cells, Leydig cells, and uterine endometrial glands) were present at 4 years of age and beyond. Renal adenoma, uterine leiomyoma, and Leydig cell tumor were observed in several microminipigs. Moreover, glomerulosclerosis, renal interstitial fibrosis, thymic involution, and adrenocortical cell vacuolation were common in aging microminipigs. Since knowledge of age-related changes is helpful for pathologists, the basic information obtained in this study will be a useful reference for all future toxicity evaluations in microminipigs.

Abstract 6: Heterozygous TGFβ1 Zinc-Finger Knockout Dahl S Rats Reveal Protection Against High-Salt Induced Renal Injury

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Chun Cheng Andy Chen ◽  
Aron Geurts ◽  
Howard J Jacob ◽  
Fan Fan ◽  
Richard J Roman
Keyword(s):  
Blood Pressure ◽  
Zinc Finger ◽  
Interstitial Fibrosis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Renal Medulla ◽  
High Salt ◽  
Glomerular Injury ◽  
Renal Interstitial Fibrosis ◽  
Protein Excretion

We used a zinc-finger nuclease strategy to create heterozygous TGFβ1 knockout rats (TGFβ1 +/- ) on a Dahl SS/Jr genetic background with a 22 base-pair frame shift mutation between nucleotides 191-212 which introduced a premature stop codon at amino acid 34. Intercrossing TGFβ1 +/- rats did not produce homozygous knockout rats, indicating that the mutation is embryonic lethal. Wildtype (WT) littermates and TGFβ1 +/- rats were fed either a 0.4% (normal salt, NS) or 8% NaCl (high salt, HS) diet for 5 weeks. When fed a NS diet, WT and TGFβ1 +/- exhibit similar renal cortical TGFβ1 expression (1.00±0.12 vs 1.05±0.05, arbitrary units), urinary TGFβ1 excretion (3.9±1.2 vs 5.3±0.4, μg/day), proteinuria (43±5 vs 36±4, mg/day), and minimal glomerular injury and tubulointerstitial fibrosis (TIF). 5 weeks of HS increased renal cortical TGFβ1 protein expression to a greater extent in WT versus TGFβ1 +/- (1.89±0.14 vs 1.52±0.09, arbitrary units) and TGFβ1 levels in urine increased to a greater extent in WT (41±10 μg/day) versus TGFβ1 +/- rats (18±4 μg/day) fed a HS diet for 1 week. Systolic blood pressure (SBP), measured by tail-cuff, was similar in WT (161±6 mmHg) and TGFβ1 +/- (162±7 mmHg) fed a NS diet and increased to the same extent in both WT (235±2 mmHg) and TGFβ1 +/- (239±4 mmHg) fed a HS diet for 5 weeks. Urinary protein excretion increased to a greater extent in WT versus TGFβ1 +/- (463±28 vs 313±36 mg/day) fed a HS diet for 5 weeks. Glomerular injury and renal cortical interstititial fibrosis were markedly reduced in TGFβ1 +/- versus WT after 5 weeks on a HS diet. Similarly, TIF in the renal medulla was less in TGFβ1 +/- compared with WT. These findings suggest that loss of one copy of the TGFβ1 gene blunts the increase in renal TGFβ1 protein in Dahl S rats fed a HS diet and slows the progression of proteinuria, glomerulosclerosis, and renal interstitial fibrosis independent of changes in blood pressure.

scholarly journals The Impact of Bone on the Biology of Aging

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 740-740
Author(s):  
Gerard Karsenty
Keyword(s):  
Muscle Function ◽  
Male Fertility ◽  
Leydig Cells ◽  
Memory Loss ◽  
Age Related ◽  
Systematic Exploration ◽  
Biology Of Aging ◽  
The Impact ◽  
The Brain ◽  
Regulate Energy Metabolism

Abstract We hypothesized that bone may secrete hormones that regulate energy metabolism and reproduction. Testing this hypothesis revealed that the osteoblast-specific secreted protein osteocalcin is a hormone regulating glucose homeostasis and male fertility by signaling through a GPCR, Gprc6a, expressed in pancreatic β bells and Leydig cells of the testes. The systematic exploration of osteocalcin biology, revealed that it regulates an unexpectedly large spectrum of physiological functions in the brain and peripheral organs and that it has most features of an antigeromic molecule. As will be presented at the meeting, this body of work suggests that harnessing osteocalcin for therapeutic purposes may be beneficial in the treatment of age-related diseases such as depression, age-related memory loss and the decline in muscle function seen in sarcopenia.

Immunosenescence: potential causes and strategies for reversal

2000 ◽  
Vol 28 (2) ◽  
pp. 250-254 ◽  
Author(s):  
R. Aspinall ◽  
D. Andrew
Keyword(s):  
T Cell ◽  
Immune Dysfunction ◽  
Careful Analysis ◽  
Experimental Therapy ◽  
Thymic Involution ◽  
Interleukin 7 ◽  
Cell Pool ◽  
Age Related ◽  
Peripheral T Cells ◽  
Laboratory Investigations

Age-related deterioration in immune function has been recognized in many species. In humans the clinical manifestation of such immune dysfunction is age-related increases in the susceptibility to certain infections and in the incidence of some autoimmune disease and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signalling function and in replicative ability following stimulus with antigen, mitogens or anti-CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the level of available interleukin 7. Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old cells with new output generated in the thymus. Problems to overcome in order for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

Alteration of N6-methyladenosine epitranscriptome profile in unilateral ureteral obstructive nephropathy

Epigenomics ◽  
2020 ◽  
Vol 12 (14) ◽  
pp. 1157-1173
Author(s):  
Xueyan Li ◽  
Xu Fan ◽  
Xiaoming Yin ◽  
Huajian Liu ◽  
Yi Yang
Keyword(s):  
Western Blot ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Time Dependent ◽  
Obstructive Nephropathy ◽  
Functional Importance ◽  
Renal Interstitial Fibrosis ◽  
Quantification Method ◽  
Promising Therapeutic Target ◽  
Rna Immunoprecipitation

Aim: To reveal the alterations of N6-methyladenosine (m6A) epitranscriptome profile in kidney after unilateral ureteral obstruction in mice. Materials & methods: Total renal m6A and expressions of methyltransferases and demethylases were detected by colorimetric quantification method, real-time PCR and western blot, respectively. Methylated RNA immunoprecipitation sequencing was performed to map epitranscriptome-wide m6A profile. Results: Total m6A levels were time-dependent decreased within 1 week, with the lowest level detected at day 7. A total of 823 differentially methylated transcripts in 507 genes were identified. Specifically, demethylated mRNAs selectively acted on multiple pathways, including TGF-β and WNT. Conclusion: m6A modification has a functional importance in renal interstitial fibrosis during obstructive nephropathy and might be a promising therapeutic target.

Gene expression reveals vulnerability to oxidative stress and interstitial fibrosis of renal outer medulla to nonhypertensive elevations of ANG II

2003 ◽  
Vol 284 (5) ◽  
pp. R1219-R1230 ◽  
Author(s):  
Baozhi Yuan ◽  
Mingyu Liang ◽  
Zhizhang Yang ◽  
Elizabeth Rute ◽  
Norman Taylor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Control Period ◽  
Renal Medulla ◽  
Differentially Expressed ◽  
Ang Ii ◽  
Outer Medulla ◽  
Renal Outer Medulla

The present study was designed to determine whether nonhypertensive elevations of plasma ANG II would modify the expression of genes involved in renal injury that could influence oxidative stress and extracellular matrix formation in the renal medulla using microarray, Northern, and Western blot techniques. Sprague-Dawley rats were infused intravenously with either ANG II (5 ng · kg−1 · min−1) or vehicle for 7 days ( n = 6/group). Mean arterial pressure averaged 110 ± 0.6 mmHg during the control period and 113 ± 0.4 mmHg after ANG II. The mRNA of 1,751 genes (∼80% of all currently known rat genes) that was differentially expressed (ANG II vs. saline) in renal outer and inner medulla was determined. The results of 12 hybridizations indicated that in response to ANG II, 11 genes were upregulated and 25 were downregulated in the outer medulla, while 11 were upregulated and 13 were downregulated in the inner medulla. These differentially expressed genes, most of which were not known previously to be affected by ANG II in the renal medulla, were found to group into eight physiological pathways known to influence renal injury and kidney function. Particularly, expression of several genes would be expected to increase oxidative stress and interstitial fibrosis in the outer medulla. Western blot analyses confirmed increased expression of transforming growth factor-β1 and collagen type IV proteins in the outer medulla. Results demonstrate that nonhypertensive elevations of plasma ANG II can significantly alter the expression of a variety of genes in the renal outer medulla and suggested the vulnerability of the renal outer medulla to the injurious effect of ANG II.

Anti‐renal interstitial fibrosis effect of norcantharidin is exerted through inhibition of PP2Ac‐mediated C‐terminal phosphorylation of Smad3

2020 ◽  
Vol 97 (2) ◽  
pp. 293-304
Author(s):  
Han‐wen Luo ◽  
Dan‐dan Yin ◽  
Zheng Xiao ◽  
Lu Wen ◽  
Ying‐jun Liao ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Renal Interstitial Fibrosis

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

2021 ◽  
pp. 1-11
Author(s):  
Ting-Ting Liu ◽  
Ran Luo ◽  
Yi Yang ◽  
Yi-Chun Cheng ◽  
Dan Chang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Tube Formation ◽  
Renal Interstitial Fibrosis ◽  
Genetic Ablation ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries ◽  
Renal Tubular

<b><i>Introduction:</i></b> Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. <b><i>Methods:</i></b> We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. <b><i>Results:</i></b> We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. <b><i>Conclusion:</i></b> LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

Sign in / Sign up

Export Citation Format

Share Document