The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1RC/RC mouse model of autosomal dominant polycystic kidney disease

Arroyo, Jennifer; Escobar-Zarate, Diana; Wells, Harrison H.; Constans, Megan; Thao, Ka; Smith, Jessica M.; Sieben, Cynthia J.; Martell, Madeline R.; Kline, Timothy L.; Irazabal, Maria V.; Torres, Vicente E.; Hopp, Katharina; Harris, Peter C.

doi:10.1016/j.kint.2021.01.028

Cited by 33 publications

(48 citation statements)

References 89 publications

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“…While this study does not identify a specific modifier or mechanistic link, it presents robust evidence suggesting that disease progression in C57BL/6J was less severe than in the BC or 129 mice, which are expected to be NNT-expressing. Furthermore, this same study reveals the presence of mild hydronephrosis in both BC and 129 mice but not in C57BL/6J (Arroyo et al, 2021), which is consistent with the frequent presence of hydronephrosis that we observe in N-Pkd1-KO mice.…”

Section: Discussionsupporting

confidence: 90%

“…This is especially interesting since declining GFR constitutes a fairly late consequence of cystic disease progression (Grantham et al, 2011). In line with our findings, a recent study characterized the disease progression in a mouse model homozygous for a Pkd1 hypomorphic variant on three different strain backgrounds: BalbC/cJ (BC), 129S6/SvEvTac (129) and C57BL/6J (Arroyo et al, 2021). While this study does not identify a specific modifier or mechanistic link, it presents robust evidence suggesting that disease progression in C57BL/6J was less severe than in the BC or 129 mice, which are expected to be NNT-expressing.…”

Section: Discussionsupporting

confidence: 85%

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The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

Onuchic

Padovano

Schena

et al. 2021

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Approximately 78% of cases are caused by mutations in the PKD1 gene, which encodes polycystin-1 (PC1). PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid residues of PC1 in a Pkd1-KO orthologous murine model of ADPKD dramatically suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase. This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 85%

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

Onuchic

Padovano

Schena

et al. 2021

Preprint

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“…3 The RC/RC mouse model also develops liver disease which becomes prominent in older animals and depends upon the genetic background. 38 We observed improvement in the levels of the transaminases, AST and ALT only in the 8-month-old animals which is consistent with progression of liver disease in older animals. Interestingly, treatment of CF patients with CFTR modulators leads to increased transaminase levels 39 which was not observed in our mouse studies either in younger or older animals.…”

Section: Drug Development Using Animal Modelssupporting

confidence: 81%

VX‐809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation

Yanda

Cebotaru

2021

The FASEB Journal

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Autosomal dominant polycystic kidney disease (ADPKD) is associated with the formation of renal cysts. We have devised a therapeutic approach, based on reversing the cyst phenotype from secretion to absorption by using VX-809, a modulator of the cystic fibrosis transmembrane regulator trafficking and processing.Our goal is to test VX-809 in RC/RC mice bearing the R3277C human mutation to demonstrate its therapeutic potential. We found that by 5 months of age, RC/ RC mice had large cysts and impaired renal function, but when treated with VX-809 between the ages of 3 and 5 months, or 6 and 8 months, the cyst area was reduced in both groups, suggesting that VX-809 had shrunk previously existing cysts. After 2 months of treatment, the cyst size was lower than that of untreated animals of the same age. Our co-localization studies confirmed that cystic fibrosis transmembrane conductance regulator (CFTR) is found predominately at the apical membrane in the untreated animals of each age group, consistent with its role in Cl − secretion; after VX-809 treatment, the basolateral membrane colocalization of CFTR increased ~4-fold, accompanied by a decrease of ~2-3-fold in its apical co-localization, indicating that VX-809 alters the phenotype to favor fluid absorption. Sodium/hydrogen exchanger and epithelial sodium channel, found in normal kidneys at the apical membrane, were almost absent from the cysts. VX-809 restored both levels toward normal. HSP27 is highly expressed in RC/RC mice and lowered toward normal by VX-809. Our demonstration of cyst reduction, improved renal function, and generation of an absorptive phenotype all strongly support the therapeutic potential of VX-809 as a treatment for ADPKD. We show here in an animal model of slowly progressing cyst formation typical of human ADPKD that VX-809 reduces the growth of already established cysts. The magnitude of the effect in the RC/RC mouse model when compared to previous experiments using the same mouse model to evaluate tolvaptan How to cite this article: Yanda MK, Cebotaru L. VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation.

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“…To complement the human study, evaluate the impact of dietary regimens on PKD progression in the setting of normal body weight, and to expand the dietary intervention protocols to also include TRF, we utilized the C57Bl/6J homozygous p.R3277C ( Pkd1 RC/RC ) ADPKD mouse model ( Hopp et al., 2012 ; Arroyo et al., 2021 ) which mimics the genetics and pathophysiology of the human disease. The study duration was from 3 months (mo) of age to 6mo of age.…”

Section: Resultsmentioning

confidence: 99%

Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease

et al. 2022

Self Cite

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Summary Progression of autosomal dominant polycystic kidney disease (ADPKD) is modified by metabolic defects and obesity. Indeed, reduced food intake slows cyst growth in preclinical rodent studies. Here, we demonstrate the feasibility of daily caloric restriction (DCR) and intermittent fasting (IMF) in a cohort of overweight or obese patients with ADPKD. Clinically significant weight loss occurred with both DCR and IMF; however, weight loss was greater and adherence and tolerability were better with DCR. Further, slowed kidney growth correlated with body weight and visceral adiposity loss independent of dietary regimen. Similarly, we compared the therapeutic efficacy of DCR, IMF, and time restricted feeding (TRF) using an orthologous ADPKD mouse model. Only ADPKD animals on DCR lost significant weight and showed slowed cyst growth compared to ad libitum , IMF, or TRF feeding. Collectively, this supports therapeutic feasibility of caloric restriction in ADPKD, with potential efficacy benefits driven by weight loss.

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The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1RC/RC mouse model of autosomal dominant polycystic kidney disease

Cited by 33 publications

References 89 publications

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

VX‐809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation

Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease

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