Hereditary Pancreatitis Model WBN/Kob Rat Strain Has a Unique Haplotype in the Pdwk1 Region on Chromosome 7

Mori, Masayuki; Fu, Xiaoying; Chen, Lei; Zhang, Guohong; Higuchi, Kenichi

doi:10.1538/expanim.58.409

Cited by 13 publications

(5 citation statements)

References 12 publications

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“…Mitochondrial swelling after ischemia and stasis of pancreatic juice were further reported to be responsible for early pancreatic changes [125,126]. Chromosomal mapping of WBN/Kob rats showed a unique haplotype block in the chromosomal region Pdwk1 (pancreatitis and diabetes mellitus in WBN/Kob locus 1) on chromosome 7 after identification of nucleotide polymorphisms of three candidate genes that were not found in other inbred rat strains [127]. These genes ( Rac2 , Grap2 and Xpnpep3 ) exert different functions.…”

Section: Introductionmentioning

confidence: 99%

Animal models for investigating chronic pancreatitis

Aghdassi

Mayerle

Christochowitz

et al. 2011

Fibrogenesis Tissue Repair

106

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Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.

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Section: Introductionmentioning

confidence: 99%

Animal models for investigating chronic pancreatitis

Aghdassi

Mayerle

Christochowitz

et al. 2011

Fibrogenesis Tissue Repair

106

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show abstract

“…Tsuji et al identified two highly significant QTLs for chronic pancreatitis and/or hyperinsulinemia on chromosomes 7 and X [29]. Mori et al reported that Pdwk1 (on chromosome 7) was a candidate gene for pancreatitis in the WBN/Kob rat [17].…”

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confidence: 99%

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

Akimoto

Terada

Shimizu

2012

The Journal of Veterinary Medical Science

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ABSTRACT. We established the WBN/Kob-Lepr fa rat as a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr fa rats provide a model of non-insulin-dependent diabetes, although its onset is secondary to pancreatitis. In the present study, we compared histopathological observations of pancreatitis in each genotype of this rat, to examine its suitability as a model of pancreatitis. The histopathological findings of the pancreatitis revealed intense changes dependent on age, such as hemorrhage or hemosiderin deposition. The pancreatitis in homozygous (fa/fa) WBN/Kob-Lepr fa rats were more severe than those of WBN/ Kob rats. Pancreatitis is a common disorder of the exocrine the pancreas in dogs and cats. Clinical diagnosis of chronic pancreatitis is challenging because the disease is usually mild or subclinical, and its clinical signs are often the same as those of complicating or concurrent diseases. Pancreatitis is inflammation of the pancreas introduced by autodigestion and results in leakage of digestive enzymes. In rats and mice, experimental pancreatitis can be induced by ethanol feeding, [30] Original WBN/Kob rats were the spontaneous model of the pancreatitis [22]. Male WBN/Kob rats commonly develop chronic pancreatitis by the age of 3 months, while diabetes mellitus occurs at 9 months [10,18,19,28]. In contrast to males, female rats of this strain do not show pancreatitis.The leptin receptor fatty gene (Lepr fa ) is a recessive mutation that leads to leptin receptor deficiency, and homozygous animals (fa/fa) show obesity, hyperphagia, insulin resistance, hyperinsulinemia, and glucose intolerance [5,13,27,31]. The leptin receptor fatty gene accelerates pancreatitis and diabetes in WBN/Kob-Lepr fa rats. In the present study, we compared histopathological observations of pancreatitis in each genotype, to examine the suitability of using WBN/Kob-Lepr fa rats as a model of pancreatitis. Each genotype (fa/fa, +/fa, and +/+) of WBN/Kob-Lepr fa rats was produced by mating heterozygous (+/fa) males with heterozygous (+/fa) females. Genotyping of the fa mutation was performed according to the method described by Masuyama [15]. The animals were given a commercial diet (MF, Oriental Yeast Co. Tokyo, Japan) and tap water ad libitum, and were housed in an air-conditioned room (24  2C, 50~60% relative humidity, and lights on for 14 hr per day from 6:00 to 20:00). The number of animals in each group is detailed in Table 1. At 7, 9, 11, and 13 weeks of age, a blood sample was collected for each genotype (fa/fa, +/fa, and +/+), while blood glucose levels were measured with a portable glucose meter (Asensia Breeze) (Bayer-Sankyo). Rats were then sacrificed by ether anesthesia. The pancreas was removed, fixed overnight in Bouin's solution, and embedded in paraffin for histopathological analyses. Serial 4-m sections were cut and then stained with hematoxylin-eosin for histological examination. All sections were examined histopathologically and findings were graded from norm...

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“…Diseases of exocrine pancreas such as chronic pancreatitis and AP adversely affect endocrine function and may lead to diabetes [47]. Pancreatitis and secondary diabetes are observed in WBN/KOb rats [48] and severity of pancreatitis and diabetes increases in WBN/Kob-Leprfa strain with homozygous fa/fa trait (genetic obesity), as compared to parental WBN/KOb rats. These homozygous (fa/fa) WBN/ Kob-Leprfa rats with obesity develop pancreatitis at the age of 7 -9 weeks compared to 3 months in WBN/Kob rats, and develop diabetes by the age of 3 -4 months as compared to 9 months in male WBN/Kob rats [49].…”

Section: Discussionmentioning

confidence: 99%

WNIN Mutant Obese Rats Develop Acute Pancreatitis With the Enhanced Inflammatory Milieu

Singh,

Ajumeera,

Malakapalli

et al. 2023

Cell Mol Med Res

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Background: WNIN/Gr-Ob rats demonstrate features of metabolic syndrome that include obesity, insulin resistance, impaired glucose tolerance, and hyperinsulinemia. The impetus obtained from earlier studies on these rats demonstrates an inflammatory milieu peaking between 6 and 9 months of age in adipose, pancreas, and bone marrow/mesenchymal stem cells. Methods:We evaluated the outcome of L-arginine-induced acute pancreatitis, in WNIN/Gr-Ob rats as compared to control rats. We assessed key parameters associated with severity of acute pancreatitis such as pancreatic inflammation and extra-pancretic damage. Result:We demonstrated increased pancreatic inflammation (inflammatory cytokines, malondialdehyde, and reactive oxygen species) in WNIN/Gr-Ob rats as compared to the control rats administered with L-arginine. Increased systemic inflammation and islet dysfunction were also observed in WNIN/Gr-Ob rats as compared to control when L-arginine was administered. Molecular, cellular and biochemical data from our study indicate increased severity of pancreatitis in mutant rats as compared to control rats. Conclusion:We advocate WNIN/Gr-Ob rats as a novel model system to study the pathophysiology of severe acute pancreatitis associated with obesity.

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Hereditary Pancreatitis Model WBN/Kob Rat Strain Has a Unique Haplotype in the Pdwk1 Region on Chromosome 7

Cited by 13 publications

References 12 publications

Animal models for investigating chronic pancreatitis

Animal models for investigating chronic pancreatitis

Progression of Pancreatitis Prior to Diabetes Onset in WBN/Kob-Leprfa Rats

WNIN Mutant Obese Rats Develop Acute Pancreatitis With the Enhanced Inflammatory Milieu

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