Interventions for preventing the progression of autosomal dominant polycystic kidney disease

Bolignano, Davide; Palmer, Suetonia C.; Ruospo, Marinella; Zoccali, Carmine; Craig, Jonathan C.; Strippoli, Giovanni F.M.

doi:10.1002/14651858.cd010294.pub2

Cited by 27 publications

(24 citation statements)

References 88 publications

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“…ADPKD is responsible for 5%-10% of ESRD cases (2,3). Unfortunately, treatment options for ADPKD are very limited (4). A better understanding of the pathophysiology of ADPKD is necessary for the development of more effective therapies for the management of this systemic disease.…”

Section: Introductionmentioning

confidence: 99%

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap¹,

Hein²,

Chini³

et al. 2020

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap¹,

Hein²,

Chini³

et al. 2020

JCI Insight

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“…In recent years, drugs that target these signalling pathways have been used in rodent PKD models to evaluate their potential for PKD in preclinical studies. Although rapamycin showed good efficacy in a variety of rodent PKD models, desirable therapeutic effects were not observed in humans with PKD in subsequent clinical studies (Bolignano et al, 2015). Although tolvaptan has been approved for the treatment of ADPKD, there are still some patients who cannot tolerate the side effects such as liver damage.…”

Section: Introductionmentioning

confidence: 99%

The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease

Lian

et al. 2019

British J Pharmacology

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Background and Purpose The pathogenic mechanism of autosomal dominant polycystic kidney disease (ADPKD) is unclear. Similar to tumour cells, polycystic kidney cells are primarily dependent on aerobic glycolysis for ATP production. Compared with rodents, miniature pigs are more similar to humans. This study is the first time to investigate the effects of the combination of metformin and 2‐deoxyglucose (2DG) in a pig model of chronic progressive ADPKD. Experimental Approach A miniature pig ADPKD model was established by inducible deletion of the PKD1 gene. Blood, urine and kidney biopsy specimens were collected for analysis at specific times. The renal vesicle index was analysed by three‐dimensional reconstruction of CT scans. Markers of the mammalian target of rapamycin (mTOR) and ERK signalling pathways and associated metabolism were detected by Western blots and colorimetry. Key Results The three‐dimensional reconstruction of CT scans indicated a markedly lower renal vesicle index in the combination therapy group. Each drug intervention group showed a significantly lower serum creatinine and urinary protein/creatinine ratio. This treatment regimen also inhibited the activities of markers of the proliferation‐related mTOR and ERK pathways, and the expression of key enzymes involved in glycolysis, as well as reducing the production of ATP and lactic acid. Conclusions and Implications This study showed that the combination of metformin and 2DG blocked the formation of renal cysts and improved the renal function in ADPKD miniature pigs. Our results indicate that the combination of metformin and 2DG may be a promising therapeutic strategy in human ADPKD.

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“…Using MRI-determined increases in kidney volume as a marker of disease progression, rapamycin-based regimens showed significantly reduced cystic kidney volumes when compared to alternative treatments [190,195,196]. Clinical trials using rapamycin to treat ADPKD have however produced varied results [197,198,199], though they may have been impeded by small sample size, reliance on poor markers of clinical progression, short follow up time for such a slow-progressing disease, and insufficient rapamycin doses [200]. …”

Section: Ageing and Age-related Pathologies Amenable To Treatment mentioning

confidence: 99%

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Walters

Cox

2018

IJMS

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Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

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Interventions for preventing the progression of autosomal dominant polycystic kidney disease

Cited by 27 publications

References 88 publications

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

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