Rapamycin Delays But Does Not Prevent Recovery from Acute Renal Failure: Role of Acquired Tubular Resistance

Lieberthal, Wilfred; Fuhro, Robert; Andry, Chris; Patel, Vimal; Levine, Jerrold S.

doi:10.1097/01.tp.0000225772.22757.5e

Cited by 56 publications

(51 citation statements)

References 33 publications

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“…17 mTOR phosphorylates and inhibits the kinases ULK1/2, catalytic subunits of a protein kinase complex that initiates the autophagic cascade. 26,27 Similar to reports by Lieberthal et al, 28,29 we showed activation of mTORC1 in the proximal tubules of the postischemic kidneys. At 3 days after IRI, cells with mTORC1 activation had fewer RFP puncta.…”

Section: Discussionsupporting

confidence: 78%

“…These results are consistent with the study showing that rats receiving rapamycin treatment had a lower rate of tubular proliferation and delayed recovery of renal function after ischemic injury. 28 In mice with cisplatininduced AKI, however, rapamycin treatment led to a modest but statistically significant reduction in BUN and creatinine and a better renal morphology. The beneficial effect was related to the increase in LC3-II levels at 2 days after cisplatin injection, suggesting that early activation of autophagy during the injury phase protected against chemical toxicity.…”

Section: Discussionmentioning

confidence: 99%

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New Autophagy Reporter Mice Reveal Dynamics of Proximal Tubular Autophagy

Wang²,

Hill

et al. 2014

Journal of the American Society of Nephrology

160

173

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The accumulation of autophagosomes in postischemic kidneys may be renoprotective, but whether this accumulation results from the induction of autophagy or from obstruction within the autophagic process is unknown. Utilizing the differential pH sensitivities of red fluorescent protein (RFP; pK a 4.5) and enhanced green fluorescent protein (EGFP; pK a 5.9), we generated CAG-RFP-EGFP-LC3 mice to distinguish early autophagic vacuoles from autolysosomes. In vitro and in vivo studies confirmed that in response to nutrient deprivation, renal epithelial cells in CAG-RFP-EGFP-LC3 mice produce autophagic vacuoles expressing RFP and EGFP puncta. EGFP fluorescence diminished substantially in the acidic environment of the autolysosomes, whereas bright RFP signals remained. Under normal conditions, nephrons expressed few EGFP and RFP puncta, but ischemia-reperfusion injury (IRI) led to dynamic changes in the proximal tubules, with increased numbers of RFP and EGFP puncta that peaked at 1 day after IRI. The number of EGFP puncta returned to control levels at 3 days after IRI, whereas the high levels of RFP puncta persisted, indicating autophagy initiation at day 1 and autophagosome clearance during renal recovery at day 3. Notably, proliferation decreased in cells containing RFP puncta, suggesting that autophagic cells are less likely to divide for tubular repair. Furthermore, 87% of proximal tubular cells with activated mechanistic target of rapamycin (mTOR), which prevents autophagy, contained no RFP puncta. Conversely, inhibition of mTOR complex 1 induced RFP and EGFP expression and decreased cell proliferation. In summary, our results highlight the dynamic regulation of autophagy in postischemic kidneys and suggest a role of mTOR in autophagy resolution during renal repair.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

New Autophagy Reporter Mice Reveal Dynamics of Proximal Tubular Autophagy

Wang²,

Hill

et al. 2014

Journal of the American Society of Nephrology

160

173

View full text Add to dashboard Cite

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“…However, by day 7 after IRI induction there was no significant difference in BUN level between experimental groups. Similar effects have been reported in the work of Lieberthal et al [27], who found no differences in kidney function on day 7 after induced IRI between non-treated and rapamycin-treated rats, but by day 6 after induced IRI, rapamycin-treated animals had lower GFR and worse histology score. It is important to note that when renal function was explored 30 days after induced renal IRI in rats, it was found that rapamycin prevented GFR decline [28].…”

Section: Discussionsupporting

confidence: 75%

Effects of Everolimus on Oxidative Stress in Kidney Model of Ischemia/Reperfusion Injury

Kezic¹,

Thaiss²,

Becker

et al. 2013

Am J Nephrol

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Background/Aims: Reactive oxygen species play an important role in the pathogenesis of kidney ischemia/reperfusion injury (IRI) which may be influenced by immunosuppressive therapy. Pertinent to this, we investigated the effects of the mTOR inhibitor everolimus on redox settings and the activity of the anti-oxidative system in kidneys exposed to IRI. Methods: C57BL/6 mice were subjected to IRI by clamping both renal pedicles for 45 min. Everolimus was applied in daily, subcutaneous doses (0.25 mg/kg body weight), starting 1 day before IRI induction. Both everolimus-treated and non-treated mice were sacrificed at several time points, starting 30 min and finishing 7 days after IRI induction. Markers of oxidation such as glutathione and NADPH levels and anti-oxidative enzyme activities were determined in the kidneys. Results: In comparison to both sham and non-treated animals, the treatment with everolimus resulted in an increased level of markers of oxidation, including a lower level of glutathione, increased level of oxidized glutathione and reduced level of NADPH. The activity of superoxide dismutase was reduced in both experimental groups, but the effects were less pronounced in everolimus-treated animals. In the early phase of reperfusion, everolimus-treated animals showed higher activity of glutathione reductase in comparison to non-treated animals, whereas the activities of glutathione peroxidase and catalase were generally similar. The treatment with everolimus significantly reduced heme oxygenase-1 expression and increased iNOS mRNA expression when compared to non-treated animals. Conclusion: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.

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“…This finding is in line with a recent report demonstrating reduced cytoprotective capacity under everolimus treatment in I/R in rats (36). In the 48 h after I/R, mTORC1-deficient tubules showed a reduced proliferative response, corresponding with the documented delayed graft function in kidney transplant patients treated with mTORC1 inhibitors (20,21).…”

Section: Discussionsupporting

confidence: 81%

“…Mice treated with rapamycin can develop a Fanconi-like proximal tubular injury pattern consisting of glucosuria, amino aciduria, and phosphaturia (19), whereas renal transplant patients receiving mTOR inhibitors early after transplantation experience increased rates of delayed graft function (20). A prolonged recovery after ischemia/reperfusion (I/R) injury also is observed commonly in animals treated with rapamycin (21). Despite the assumption that these perturbations are related to the direct effects of mTOR inhibitors on tubular epithelial cells in the kidney, it has been difficult to differentiate these findings from the systemic effects of mTOR inhibitors.…”

mentioning

confidence: 99%

mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress

Grahammer

Haenisch

Steinhardt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are commonly used as immunosuppressants in solid-organ transplantation and as antiproliferative agents in various cancers. Despite indications of serious renal adverse events caused by mTORC1 inhibition, the role of mTORC1 for renal epithelial function and homeostasis has remained elusive. Unexpectedly, tubular mTORC1 controls energy-driven urine-concentrating mechanisms by maintaining mitochondrial biogenesis. Under pathophysiological conditions, mTORC1-dependent mitochondrial biogenesis is essential for energy supply and adaptation in response to ischemia. These findings identify mTORC1 as an important regulator of tubular energy metabolism, transcellular transport processes, and ischemic stress responses.

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Rapamycin Delays But Does Not Prevent Recovery from Acute Renal Failure: Role of Acquired Tubular Resistance

Abstract: Rapamycin delays but does not prevent renal recovery after ARF. MPT cells become resistant to rapamycin after prolonged exposure. We speculate that the ultimate recovery of renal function after ARF is due to the development of acquired tubular cell resistance to rapamycin.

Cited by 56 publications

References 33 publications

New Autophagy Reporter Mice Reveal Dynamics of Proximal Tubular Autophagy

New Autophagy Reporter Mice Reveal Dynamics of Proximal Tubular Autophagy

Effects of Everolimus on Oxidative Stress in Kidney Model of Ischemia/Reperfusion Injury

mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress

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