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Project
Autosomal Dominant Polycystic Kidney Disease: From bedside to bench and back
Autosomal dominant polycystic kidney disease (ADPKD) is the most commonmonogenic disorder leading ultimately to end-stage renal disease (ESRD). It is caused by loss-of-function mutations in either the PKD1</> (85%)or PKD2</> (15%) genes which encode polycystin-1 (PC1) and -2 (PC2), respectively. Patients with PKD2</> mutations have a milder phenotype and reach ESRD ~20 years later than those with PKD1</> mutations. Clinical and fundamental-research data suggest several potential mechanisms that could lead to cyst formation in ADPKD. </>Among these, the most prominent aberrant signaling pathways involved are Ca2+, the mammalian target of rapamycin (mTOR) and cAMP. Cells from ADPKD cysts display alterations in cellular Ca2+ signaling and were reported to have a reduced resting cytosolic Ca2+ level. Also, the mTOR activity is enhanced in these cells, and an increased level of cAMP is a common finding in several animal models for ADPKD. Based on these cellular mechanisms, new drug targetswere tested in vitro</> and in vivo</> to slow the cystogenesis. However, most clinical trials have been limited by inadequate power, short follow-up, wide ranges of renal function, doses with inadequate pharmacological effects and uncertain concentration in the target organs. Moreover,there is an imbalance between the actual beneficial effect of the used drugs and their potential side effects. Therefore, dosing strategies areneeded to be optimized. Also, screening of patients in families with a positive history of ADPKD remains a matter of controversy. The argumentsagainst such screening are possible psychological stress and the inability to obtain life or medical insurance if ADPKD is detected, and, on the other hand, the absence of effective treatment for preventing cyst formation and growth. </>
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In this thesis, we showed that the presence of both PC1 and PC2 was required to stimulate the inositol 1,4,5-trisphosphate receptor, an ubiquitous intracellular Ca2+-release channel. Both PCs interacted with each other and operated as a signaling complex in affecting cellular Ca2+. Next, we found striking and novel differences in cells with either PC1 or PC2 deficiency. The level of free cytosolic Ca2+ was decreased in PC1-deficient cells but slightly increasedin PC2-deficient cells. In contrast to PC1 deficiency, PC2-deficient cells did not display inhibition of the AMP-dependent kinase (AMPK), nor activation of the mTORC1 kinase. ERK1/2 and Akt activity, on the other hand, were similarly affected in PC1- and PC2-deficient cells. Next, we exploited these novel insights to potentiate the rapamycin-induced inhibition of the excessive mTOR activity in PC1-deficient cells by boosting the activity of AMPK, an endogenous negative regulator of mTOR. We therebyused metformin, an AMPK-activating drug used for the treatment of diabetes type-2 patients. Our data revealed a synergistic effect: a combination of rapamycin and metformin was more efficient for suppressing mTOR activity in PC1-deficient cells than either drug alone. These data providenovel therapeutic strategies to sensitize PC1-deficient cells towards rapamycin via</> an additional drug that is already clinically used. By using much lower rapamycin doses in ADPKD patients with PKD1</> mutations, it might be possible to avoid potential adverse effects without compromising the clinical outcome. </>
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We also demonstrated that the morbidity in children with ADPKD diagnosed by screening and in those presenting with symptoms, was similar. Therefore, we pointed out theneed of screening children with a family history of ADPKD, to monitor their blood pressure and urine albumin, and to treat these modifiable risk factors by starting appropriate therapies in order to minimize the cardiovascular risks. </>
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In conclusion, our results provide novel mechanistic insights, and they reveal common aspects as well as differences in the molecular mechanisms underlying ADPKD associated witheither PKD1</> or PKD2 </>mutations. These data may lead to an optimized design of novel therapies in future clinical trials. We also argue fora good selection of patients with characterization of their genetic background and an inclusion of young patients before irreversible damage has occurred. Furthermore, we found evidence that a combination of different drugs at low doses might provide a synergistic effect. Future clinical trials should reveal if this could allow a life-long treatment of ADPKD patients with less side effects. </></></>
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In this thesis, we showed that the presence of both PC1 and PC2 was required to stimulate the inositol 1,4,5-trisphosphate receptor, an ubiquitous intracellular Ca2+-release channel. Both PCs interacted with each other and operated as a signaling complex in affecting cellular Ca2+. Next, we found striking and novel differences in cells with either PC1 or PC2 deficiency. The level of free cytosolic Ca2+ was decreased in PC1-deficient cells but slightly increasedin PC2-deficient cells. In contrast to PC1 deficiency, PC2-deficient cells did not display inhibition of the AMP-dependent kinase (AMPK), nor activation of the mTORC1 kinase. ERK1/2 and Akt activity, on the other hand, were similarly affected in PC1- and PC2-deficient cells. Next, we exploited these novel insights to potentiate the rapamycin-induced inhibition of the excessive mTOR activity in PC1-deficient cells by boosting the activity of AMPK, an endogenous negative regulator of mTOR. We therebyused metformin, an AMPK-activating drug used for the treatment of diabetes type-2 patients. Our data revealed a synergistic effect: a combination of rapamycin and metformin was more efficient for suppressing mTOR activity in PC1-deficient cells than either drug alone. These data providenovel therapeutic strategies to sensitize PC1-deficient cells towards rapamycin via</> an additional drug that is already clinically used. By using much lower rapamycin doses in ADPKD patients with PKD1</> mutations, it might be possible to avoid potential adverse effects without compromising the clinical outcome. </>
</>
We also demonstrated that the morbidity in children with ADPKD diagnosed by screening and in those presenting with symptoms, was similar. Therefore, we pointed out theneed of screening children with a family history of ADPKD, to monitor their blood pressure and urine albumin, and to treat these modifiable risk factors by starting appropriate therapies in order to minimize the cardiovascular risks. </>
</>
In conclusion, our results provide novel mechanistic insights, and they reveal common aspects as well as differences in the molecular mechanisms underlying ADPKD associated witheither PKD1</> or PKD2 </>mutations. These data may lead to an optimized design of novel therapies in future clinical trials. We also argue fora good selection of patients with characterization of their genetic background and an inclusion of young patients before irreversible damage has occurred. Furthermore, we found evidence that a combination of different drugs at low doses might provide a synergistic effect. Future clinical trials should reveal if this could allow a life-long treatment of ADPKD patients with less side effects. </></></>
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Date:5 Jan 2009 → 13 Dec 2012
Keywords:polo-like kinase-1, apoptosis, polycystic kidney disease, ADPKD, mTOR, Ca2+ signalling, Autophagy
Disciplines:Physiology, Biophysics
Project type:PhD project