Modification of disease progression in rats with inherited polycystic kidney disease

Cowley, Benjamin D.; Grantham, Jared J.; Muessel, Michelle J.; Kraybill, Amy L.; Gattone, Vincent H.

doi:10.1016/s0272-6386(96)90525-9

Cited by 56 publications

(33 citation statements)

References 32 publications

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“…[7][8][9][10] Biochemical measurements taken at the time of euthanasia in this study are consistent with our previous publications in this model. 7,8,11,12 Table 1 shows that the CKD rats had elevated BUN, phosphorus, and fibroblast growth factor 23 (FGF23) compared with normal (NL) rats.…”

Section: Assessment Of Ckdsupporting

confidence: 92%

“…This animal model spontaneously develops manifestations of CKD, including biochemical abnormalities and reduced GFR, including hypertension, left ventricular hypertrophy, renal osteodystrophy, and arterial calcification. [7][8][9][10] Cy/+ rats (called CKD) were 35 weeks old, with the exception of one animal studies at 39 weeks. On the basis of previous 24-hour urine collections, 8 the GFR at 35 weeks is approximately 10%-20%.…”

Section: Animal Modelmentioning

confidence: 99%

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Pathogenesis of Arrhythmias in a Model of CKD

Hsueh

Chen²,

Lin

et al. 2014

Journal of the American Society of Nephrology

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Patients with CKD have an increased risk of cardiovascular mortality from arrhythmias and sudden cardiac death. We used a rat model of CKD (Cy/+) to study potential mechanisms of increased ventricular arrhythmias. Rats with CKD showed normal ejection fraction but hypertrophic myocardium. Premature ventricular complexes occurred more frequently in CKD rats than normal rats (42% versus 11%, P=0.18). By optical mapping techniques, action potential duration (APD) at 80% of repolarization was longer in CKD rats (7864ms) than normal rats (6363 ms, P,0.05) at a 200-ms pacing cycle length. Calcium transient (CaT) duration was comparable. Pacing cycle length thresholds to induce CaT alternans or APD alternans were longer in CKD rats than normal rats (10067 versus 8063 ms and 9366 versus 7664 ms for CaT and APD alternans, respectively, P,0.05), suggesting increased vulnerability to ventricular arrhythmia. Ventricular fibrillation was induced in 9 of 12 CKD rats and 2 of 9 normal rats (P,0.05); early afterdepolarization occurred in two CKD rats but not normal rats. The mRNA levels of TGF-b, microRNA-21, and sodium calcium-exchanger type 1 were upregulated, whereas the levels of microRNA-29, L-type calcium channel, sarco/endoplasmic reticulum calcium-ATPase type 2a, Kv1.4, and Kv4.3 were downregulated in CKD rats. Cardiac fibrosis was mild and not different between groups. We conclude that cardiac ion channel and calcium handling are abnormal in CKD rats, leading to increased vulnerability to early afterdepolarization, triggered activity, and ventricular arrhythmias. CKD affects more than 26 million individuals; 15% of American adults have some degree of CKD. 1 Cardiovascular events account for 40% of deaths in CKD patients. In patients on dialysis, 25% of cardiovascular deaths are caused by sudden cardiac death, a 100-fold rate compared with the general population. 2,3 Although the increased frequency in dialysis patients has often been attributed to electrolyte imbalances induced by the dialysis procedure in patients with underlying cardiac disease, recent data have highlighted the increased risk with CKD in patients not yet on dialysis, indicating that other factors in these patients with CKD may lead to sudden cardiac death. 4 The Multicenter Automatic Defibrillator Implantation Trial-II showed that the risk for sudden cardiac death was 17% higher for every 10 ml/min per 1.73 m 2 decrease in eGFR. 5 The result was comparable even when patients considered low risk for sudden cardiac death were analyzed. 6 The pathogenesis by which CKD predisposes to sudden cardiac death remains unknown. Our rat model of CKD, the Cy/+ rat, accurately represents many of the changes associated with human CKD, including hypertension, left ventricular hypertrophy, and CKD-mineral bone disorder. Furthermore, we have occasionally

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Section: Assessment Of Ckdsupporting

confidence: 92%

Section: Animal Modelmentioning

confidence: 99%

Pathogenesis of Arrhythmias in a Model of CKD

Hsueh

Chen²,

Lin

et al. 2014

Journal of the American Society of Nephrology

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“…The first study was the one by Aukema et al, who demonstrated that early dietary protein restriction could reduce cyst development and slow down disease progression in a murine model of PKD [77]. Similar results were obtained in other experimental studies [78,79], and low-protein diet also proved to lengthen survival in PKD mice [80]. Banković-Calić et al showed that low casein and soy feeding ameliorates renal histological injury in a rat model of PKD by reducing tubular remodeling, interstitial inflammation and fibrosis [81].…”

Section: Adpkd and Dietsupporting

confidence: 59%

An overview of experimental and early investigational therapies for the treatment of polycystic kidney disease

Santoro

Pellicanò

Visconti

et al. 2015

Expert Opinion on Investigational Drugs

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Among the drugs currently being explored, mammalian target of rapamycin inhibitors reduce kidney volume enlargement but their role remains uncertain. The most promising drug is the V2 receptor antagonist tolvaptan, which reduces the increased rate of total kidney volume and slows down glomerular filtration rate decline. The main candidates for the treatment of cysts growth, both in the kidney and in the liver whenever present, are the somatostatin analogues, such as lanreotide and octreotide and more recently pasireotide. As for other therapies, some favorable results have been achieved but data are still not sufficient to establish if these approaches may be beneficial in slowing ADPKD progression in the future.

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“…While Cys1 cpk mice heterozygote for the Cux1 tm1Ejn mutation showed a slight increase in KW/BW, it was not significant. Large cystic kidneys are directly correlated with reduced renal function and high BUN levels (13,62). Accordingly, Cux1 tm1Ejn /Cys1 cpk animals had higher BUN levels than Cys1 cpk mice (Fig.…”

Section: Resultsmentioning

confidence: 90%

Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cux1

Alcalay

Sharma²,

Vassmer³

et al. 2008

American Journal of Physiology-Renal Physiology

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Polycystic kidney diseases (PKD) are inherited as autosomal dominant (ADPKD) or autosomal recessive (ARPKD) traits and are characterized by progressive enlargement of renal cysts. Aberrant cell proliferation is a key feature in the progression of PKD. Cux1 is a homeobox gene that is related to Drosophila cut and is the murine homolog of human CDP (CCAAT Displacement Protein). Cux1 represses the cyclin kinase inhibitors p21 and p27, and transgenic mice ectopically expressing Cux1 develop renal hyperplasia. However, Cux1 transgenic mice do not develop PKD. Here, we show that a 246 amino acid deletion in Cux1 accelerates PKD progression in cpk mice. Cystic kidneys isolated from 10-day-old cpk/Cux1 double mutant mice were significantly larger than kidneys from 10-day-old cpk mice. Moreover, renal function was significantly reduced in the Cux1 mutant cpk mice, compared with cpk mice. The mutant Cux1 protein was ectopically expressed in cyst-lining cells, where expression corresponded to increased cell proliferation and apoptosis, and a decrease in expression of the cyclin kinase inhibitors p27 and p21. While the mutant Cux1 protein altered PKD progression, kidneys from mice carrying the mutant Cux1 protein alone were phenotypically normal, suggesting the Cux1 mutation modifies PKD progression in cpk mice. During cell cycle progression, Cux1 is proteolytically processed by a nuclear isoform of the cysteine protease cathepsin-L. Analysis of the deleted sequences reveals that a cathepsin-L processing site in Cux1 is deleted. Moreover, nuclear cathepsin-L is significantly reduced in both human ADPKD cells and in Pkd1 null kidneys, corresponding to increased levels of Cux1 protein in the cystic cells and kidneys. These results suggest a mechanism in which reduced Cux1 processing by cathepsin-L results in the accumulation of Cux1, downregulation of p21/p27, and increased cell proliferation in PKD.

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Modification of disease progression in rats with inherited polycystic kidney disease

Cited by 56 publications

References 32 publications

Pathogenesis of Arrhythmias in a Model of CKD

Pathogenesis of Arrhythmias in a Model of CKD

An overview of experimental and early investigational therapies for the treatment of polycystic kidney disease

Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cux1

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