Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

Novalić, Zlata; Wal, Annemieke M. van der; Leonhard, Wouter N.; Koehl, Gudrun E.; Breuning, Martijn H.; Geissler, Edward K.; Heer, Emile de; Peters, Dorien J.M.

doi:10.1681/asn.2011040340

Cited by 83 publications

(83 citation statements)

References 39 publications

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“…[25][26][27] Also, activation of AKT and ERK1/2 has been associated with cystic disease, and analysis of phosphorylated CREB has been used before as a readout for cAMP, an important second messenger involved in PKD. [28][29][30][31][32][33] In addition, Ki-67 expression was analyzed as a marker for proliferation. Indeed, the expression of these proteins was frequently elevated in tissue near cysts compared with tissue more distant to cysts.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we performed immunohistochemistry to analyze phospho-STAT3 (pSTAT3), phospho-CREB, phospho-AKT, phospho-ERK1/2, and LCN2 expressions, which have been shown to be involved in PKD. 18,[23][24][25][26][27][28][29][30][31][32][33] The clustered distribution of cysts in an iKsp-Pkd1 del,lox mouse that was treated with low-dose tamoxifen, unilateral nephrectomy, and DCVC and euthanized 6 months after tamoxifen treatment (clustering is shown in Figure 6A), indeed, cooccurred with increased expression of these proteins specifically near cysts or clusters of cysts ( Figure 6B). We quantified the number of cysts/clusters that showed this effect in renal sections at two different locations in the kidneys of seven other mildly affected mice.…”

Section: Evidence For a Cystic Snowball Effectmentioning

confidence: 90%

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Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

Leonhard

Zandbergen²,

Veraar³

et al. 2015

Journal of the American Society of Nephrology

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In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury. However, this hypothesis is primarily on the basis of animal studies, in which the gene is inactivated simultaneously in large percentages of kidney cells. To mimic human ADPKD in mice more precisely, we reduced the percentage of Pkd1-deficient kidney cells to 8%. Notably, no pathologic changes occurred for 6 months after Pkd1 deletion, and additional renal injury increased the likelihood of cyst formation but never triggered rapid PKD. In mildly affected mice, cysts were not randomly distributed throughout the kidney but formed in clusters, which could be explained by increased PKD-related signaling in not only cystic epithelial cells but also, healthy-appearing tubules near cysts. In the majority of mice, these changes preceded a rapid and massive onset of severe PKD that was remarkably similar to human ADPKD. Our data suggest that initial cysts are the principal trigger for a snowball effect driving the formation of new cysts, leading to the progression of severe PKD. In addition, this approach is a suitable model for mimicking human ADPKD and can be used for preclinical testing.

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Section: Discussionmentioning

confidence: 99%

Section: Evidence For a Cystic Snowball Effectmentioning

confidence: 90%

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

Leonhard

Zandbergen²,

Veraar³

et al. 2015

Journal of the American Society of Nephrology

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“…Many reports have indicated that cystogenesis results from multiple mechanisms, such as cAMP accumulation, aberrant MAPK signaling, or altered activation of mammalian target of rapamycin (mTOR), Jak2-STAT1/3, nuclear factor (NF)-B, and vascular endothelial growth factor signaling (2,3).…”

Section: Autosomal Dominant Polycystic Kidney Disease (Adpkd)mentioning

confidence: 99%

“…Rapamycin has been applied to various animal models to evaluate its therapeutic effect on ADPKD. It had a dramatic curative effect on ADPKD in preclinical trials (3,4). However, two independent clinical trials showed a failure to curtail cyst growth (5,6).…”

Section: Autosomal Dominant Polycystic Kidney Disease (Adpkd)mentioning

confidence: 99%

Targeting of Receptor for Advanced Glycation End Products Suppresses Cyst Growth in Polycystic Kidney Disease

Park

Kim

Lee

et al. 2014

Journal of Biological Chemistry

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Background: Receptor of advanced glycation end product (RAGE) mediates not only proinflammatory signaling, but also stimulates cell proliferation and survival-related signaling. Results: Inhibiting RAGE resulted in slowed cyst growth in an autosomal dominant polycystic kidney disease (ADPKD) mouse model and improved renal function. Conclusion: RAGE inhibition is highly effective against cyst enlargement in vivo. Significance: RAGE signaling may play a role in cystogenesis and could be a new therapeutic target for PKD.

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“…Experimental therapies for ADPKD (11,12) include rapamycin, a mammalian target of rapamycin (mTOR) inhibitor (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Prolonged rapamycin treatment inhibits not only mTOR complex 1 (mTORC1, raptor) activity but also mTOR complex 2 (mTORC2, rictor) assembly and Akt/protein kinase B (13,14).…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease

Braun

Schold

Stephany

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in 125 I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily.Design, setting, participants, & measurements In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (.5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography.Results Change in iGFR at 12 months was significantly higher in the LD group (7.7612.5 ml/min per 1.73 m 2 ; n=9) than in the SC group (211.269.1 ml/min per 1.73 m 2 ; n=9) (LD versus SC: P,0.01). Change in iGFR at 12 months in the STD group (1.6612.1 ml/min per 1.73 m 2 ; n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P,0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range6SD, 2.4060.64 to 2.9061.20 ng/ml) compared with those in the STD group (3.9362.27 to 5.7761.06 ng/ml) (P,0.01). ConclusionPatients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.

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Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

Cited by 83 publications

References 39 publications

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

Targeting of Receptor for Advanced Glycation End Products Suppresses Cyst Growth in Polycystic Kidney Disease

Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease

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