Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease.
ABSTRACT The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered.
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ABSTRACT: Inherited cystic kidney diseases, including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), are the most common monogenetic causes of end-stage renal disease (ESRD) in children and adults. While ARPKD is a rare and usually severe pediatric disease, the more common ADPKD typically shows a slowly progressive course leading to ESRD in adulthood. At the present time there is no established disease-modifying treatment for either ARPKD or ADPKD. Various therapeutic approaches are currently under investigation, such as V2 receptor antagonists, somatostatins, and mTOR inhibitors. Renal function remains stable for decades in ADPKD, and thus clinically meaningful surrogate markers to assess therapeutic efficacy are needed. Various studies have pointed out that total kidney volume (TKV) is a potential surrogate parameter for disease severity in ADPKD. Recent trials have therefore measured TKV by magnet resonance imaging (MRI) to monitor and to predict disease progression. Here, we discuss novel insights on polycystic kidney disease (PKD), the value of MRI, and the measurement of TKV in the diagnosis and follow-up of PKD, as well as novel emerging therapeutic strategies for ADPKD.Pediatric Nephrology 12/2012; · 2.94 Impact Factor
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ABSTRACT: The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of PLD and PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell proliferation. We also show that blocking PLD activity enhanced the sensitivity of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate that targeting mTOR did not induce autophagy, whereas targeting PLD induced autophagosome formation. Taken together, our findings suggest that deregulated mTOR pathway activation is mediated partly by increased PLD signaling in PKD cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new therapeutic strategy in PKD.PLoS ONE 01/2013; 8(8):e73173. · 3.73 Impact Factor
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ABSTRACT: SUMMARY AT A GLANCE: Stayner et al. investigated the effect of rapamycin on polycystic kidney disease in utero. Their data showed the potential beneficial effects of rapamycin administered during pregnancy in a rodent model of PKD, while cyst number remains unchanged; the size of the cysts is reduced by rapamycin treatment. Furthermore, they also showed that the inhibition of the mTOR pathway by rapamycin most likely are not mediated via pax2 in their experimental animal model. The result provides evidence of rapamycin may be therapeutically useful for slowing the progression of PKD with a prenatal onset. ABSTRACT: Aim: Polycystic kidney disease (PKD) in humans encompasses a group of disorders featuring kidney cyst expansion within the first decade (recessive PKD) or beyond the fourth to fifth decade of life (dominant PKD). Autosomal dominant PKD (ADPKD) is caused by mutations in PKD1 or PKD2 genes, and involves cyst formation beginning in utero. Like recessive PKD, ADPKD leads to end-stage kidney disease. Inhibition of mTOR signaling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in fetal Pkd1homozygous mutant mice. Methods: Pregnant Pkd1(+/-) female mice (mated with Pkd1(+/-) males) were treated with rapamycin from E14.5 to E17.5. Fetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2. Results: Numerous cysts were present in Pkd1(-/-) kidneys, which were twice the weight of wildtype kidneys. Cyst size was reduced by a third in rapamycin treated Pkd1(-/-) kidney sections and kidney mass was reduced to near wildtype levels. However, some lethality was observed in Pkd1(-/-) null embryos. Moreover, total cyst number was not reduced compared to control embryos. Pax2 expression and kidney development were unaltered in rapamycin treated mice. Conclusion: Rapamycin treatment reduces cyst formation in utero in Pkd1(-/-) mutant mice, therefore the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. In contrast, selective rapamycin-associated lethality would likely limit its usefulness as a treatment in utero. © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.Nephrology 06/2012; · 1.69 Impact Factor