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Recycling to discover something new: the role of autophagy in kidney disease
nephrology digest
www.kidney-international.org
translational science
Recycling to discover something new: the role of autophagy in kidney disease Jeremy S. Leventhal1,2, Christina M. Wyatt1 and Michael J. Ross1,2 This year, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his groundbreaking work in dissecting the mechanisms of autophagy, a cellular process resulting in the organized degradation of cytoplasmic components. Ohsumi’s work paved the way for subsequent studies that demonstrated critical roles for autophagy in modulating both acute and chronic kidney injury. This work may lead to future therapeutic approaches that target the autophagy system to prevent or treat kidney diseases. Kidney International (2017) 91, 4–6; http://dx.doi.org/10.1016/j.kint.2016.11.004 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
familiar quote attributed to Sir Isaac Newton states “If I have seen further, it is by standing on the shoulders of giants.” In October 2016, the Nobel committee anointed science’s newest giant, awarding Yoshinori Ohsumi the Nobel Prize in Physiology or Medicine for his seminal work in autophagy research. Autophagy is a general term referring to intracellular mechanisms delivering cytoplasmic substrates to lysosomes for degradation. There are 3 major subtypes of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy refers to the process by which cytoplasmic constituents or organelles are sequestered in a doublemembraned organelle called the autophagosome that fuses with a lysosome, facilitating their breakdown (Figure 1). Of the 3 mechanisms, macroautophagy is the most predominant and complicated intracellular process and is often simply referred to (as it is here) as autophagy. Christian De Duve originated the term “autophagy” in 1963 at a symposium dedicated to lysosomal study. Decades later, autophagy’s relevance to health and disease progression remained unknown. In 1992, Yoshinori Ohsumi published observations of spherical bodies containing material with the density of cytoplasm and including organelles that became sequestered within the vacuoles of yeast cells under starvation conditions.1 He hypothesized that this phenomenon was autophagy and manipulated this system with
A
1 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA; and 2 Renal Division, James J. Peters Bronx VA Medical Center, Bronx, New York, USA Correspondence: Jeremy S. Leventhal, Division of Nephrology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1243, New York, New York 10029, USA. E-mail: Jeremy.leventhal@ mssm.edu
4
protease inhibitors, resulting in accumulation of these spherical bodies, which he dubbed “autophagic bodies.”1 Ohsumi recognized the power of this simple experimental system to decipher the previously unknown mechanisms of autophagy. Soon thereafter, Ohsumi used random mutagenesis in yeast with autophagic body accumulation as his endpoint to identify the first 15 autophagyrelated genes.2 Over the ensuing years, Ohsumi deciphered autophagy’s core machinery, enabling studies of the role of autophagy in tissue homeostasis and disease. Once mammalian homologs of yeast autophagy proteins were verified, investigators began examining the role of autophagy in pulmonary, autoimmune, neurodegenerative, and cancer-related diseases.3 Accordingly, autophagy-related publications now number in the thousands (Figure 2a). Research on autophagy and kidney disease has trailed other fields but has been rapidly increasing over the past 10 years (Figure 2b). During this short period of time, our appreciation of autophagy’s role in renal physiology and disease pathogenesis has grown significantly. Early nephrology-related autophagy studies focused on the cytoprotective role of autophagy in renal tubular epithelial cells in the setting of acute kidney injury. In models of ischemia reperfusion injury, cisplatin-induced injury, and septic acute kidney injury, kidney injury was exacerbated when autophagy was inhibited using pharmacologic or genetic approaches.4 Augmenting autophagy is therefore Kidney International (2017) 91, 4–8
nephrology digest
Figure 1 | Schematic depiction of the autophagy pathway. Stressors, proinflammatory signals, and mechanistic target of rapamycin (mTOR) inhibition induce autophagy, leading to the nucleation of the phagosome membrane that surrounds cytoplasmic proteins and even whole organelles. Two conjugation systems serve to elongate the nucleation complex to form the limiting membrane. The forming limiting membrane sequesters cytosolic cargo and seals it to form an autophagosome that subsequently fuses with lysosomes in which cargo gets degraded followed by the release of nutrients to the cytosol. Autophagy can either mediate cell death or act as a prosurvival mechanism, depending on cellular contexts and stimuli. Reprinted from Schroppel B, Legendre C. Delayed graft function: from mechanism to translation. Kidney Int. 2014;86:251–258.8 Copyright ª 2014, with permission from Elsevier.
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Figure 2 | Kidney autophagy citations in PubMed. Histogram representing the total number of citations returned when searching with the term autophagy (a) and combined with kidney or renal (b). Kidney International (2017) 91, 4–8
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nephrology digest
a promising candidate approach for preventing or treating acute kidney injury. The role of autophagy in chronic kidney disease is more complex and remains controversial.5 Two recent studies using the unilateral ureteral obstruction model in mice with proximal tubule-specific deletion of autophagyrelated genes illustrate the disparate results. Livingston et al.6 reported that conditional deletion of autophagy related 7 (ATG7) in proximal tubules ameliorated renal fibrosis after unilateral ureteral obstruction as did pharmacologic inhibition of autophagy with 3-methyladenine. Conversely, similar experiments in mice with conditional deletion of autophagy related 5 (ATG5) resulted in increased interstitial fibrosis, and rapamycin, a pharmacologic inducer of autophagy, reduced unilateral ureteral obstruction–induced renal fibrosis.7 These studies suggest that autophagy has an important role in mediating and/or modulating chronic kidney injury and fibrosis. However, further research is needed to identify the optimal context in which inducing or inhibiting autophagy might prevent progressive chronic kidney disease. Most studies on the role of autophagy in kidney disease have relied on pharmacologic agents that have “off-target” effects beyond inducing or inhibiting autophagy or on genetic knockouts of autophagy-related proteins that may have developmental effects. Future studies using drugs that are more specific for autophagy and animal models with inducible
modulation of autophagy before, during, or after kidney injury are needed to determine whether targeting autophagy is a viable approach for the prevention or treatment of kidney diseases. Although we have much to learn, one can envision a future in which autophagymodifying medications are used to prevent or treat kidney diseases. If realized, this future will only be possible because of the contributions of this year’s Nobel Prize winner for Physiology or Medicine, Yoshinori Ohsumi. DISCLOSURE All the authors declared no competing interests. REFERENCES 1. Takeshige K, Baba M, Tsuboi S, et al. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 1992;119:301–311. 2. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of. Saccharomyces cerevisiae. FEBS Lett. 1993;333:169–174. 3. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–662. 4. Kaushal GP, Shah SV. Autophagy in acute kidney injury. Kidney Int. 2016;89:779–791. 5. Lenoir O, Tharaux PL, Huber TB. Autophagy in kidney disease and aging: lessons from rodent models. Kidney Int. 2016;90:950–964. 6. Livingston MJ, Ding HF, Huang S, et al. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy. 2016;12:976–998. 7. Li H, Peng X, Wang Y, et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy. 2016;12: 1472–1486. 8. Schroppel B, Legendre C. Delayed graft function: from mechanism to translation. Kidney Int. 2014;86:251–258.
chronic kidney disease
A rose by any other name: is stage 3a chronic kidney disease really a disease? Christina M. Wyatt1 1 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence: Christina M. Wyatt, Division of Nephrology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1243, New York, New York 10029, USA. E-mail: christina.wyatt@mssm. edu
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Experts have questioned the clinical relevance of early stage 3 chronic kidney disease, particularly in elderly individuals and in those without albuminuria. A recent study published in PLoS Medicine provides further evidence that many older adults with stage 3a chronic kidney disease will never worsen, whereas some may even improve. Despite limited generalizability, the results support the current, more nuanced classification of chronic kidney disease for use in clinical practice and in future epidemiologic research. Refers to: Shardlow A, McIntyre NJ, Fluck RJ, et al. Chronic kidney disease in primary care: outcomes after five years in a prospective cohort study. PLOS Med. 2016;13:e1002128. Kidney International (2017) 91, 6–8; http://dx.doi.org/10.1016/j.kint.2016.11.005 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Kidney International (2017) 91, 4–8
www.kidney-international.org
translational science
Recycling to discover something new: the role of autophagy in kidney disease Jeremy S. Leventhal1,2, Christina M. Wyatt1 and Michael J. Ross1,2 This year, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his groundbreaking work in dissecting the mechanisms of autophagy, a cellular process resulting in the organized degradation of cytoplasmic components. Ohsumi’s work paved the way for subsequent studies that demonstrated critical roles for autophagy in modulating both acute and chronic kidney injury. This work may lead to future therapeutic approaches that target the autophagy system to prevent or treat kidney diseases. Kidney International (2017) 91, 4–6; http://dx.doi.org/10.1016/j.kint.2016.11.004 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
familiar quote attributed to Sir Isaac Newton states “If I have seen further, it is by standing on the shoulders of giants.” In October 2016, the Nobel committee anointed science’s newest giant, awarding Yoshinori Ohsumi the Nobel Prize in Physiology or Medicine for his seminal work in autophagy research. Autophagy is a general term referring to intracellular mechanisms delivering cytoplasmic substrates to lysosomes for degradation. There are 3 major subtypes of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy refers to the process by which cytoplasmic constituents or organelles are sequestered in a doublemembraned organelle called the autophagosome that fuses with a lysosome, facilitating their breakdown (Figure 1). Of the 3 mechanisms, macroautophagy is the most predominant and complicated intracellular process and is often simply referred to (as it is here) as autophagy. Christian De Duve originated the term “autophagy” in 1963 at a symposium dedicated to lysosomal study. Decades later, autophagy’s relevance to health and disease progression remained unknown. In 1992, Yoshinori Ohsumi published observations of spherical bodies containing material with the density of cytoplasm and including organelles that became sequestered within the vacuoles of yeast cells under starvation conditions.1 He hypothesized that this phenomenon was autophagy and manipulated this system with
A
1 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA; and 2 Renal Division, James J. Peters Bronx VA Medical Center, Bronx, New York, USA Correspondence: Jeremy S. Leventhal, Division of Nephrology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1243, New York, New York 10029, USA. E-mail: Jeremy.leventhal@ mssm.edu
4
protease inhibitors, resulting in accumulation of these spherical bodies, which he dubbed “autophagic bodies.”1 Ohsumi recognized the power of this simple experimental system to decipher the previously unknown mechanisms of autophagy. Soon thereafter, Ohsumi used random mutagenesis in yeast with autophagic body accumulation as his endpoint to identify the first 15 autophagyrelated genes.2 Over the ensuing years, Ohsumi deciphered autophagy’s core machinery, enabling studies of the role of autophagy in tissue homeostasis and disease. Once mammalian homologs of yeast autophagy proteins were verified, investigators began examining the role of autophagy in pulmonary, autoimmune, neurodegenerative, and cancer-related diseases.3 Accordingly, autophagy-related publications now number in the thousands (Figure 2a). Research on autophagy and kidney disease has trailed other fields but has been rapidly increasing over the past 10 years (Figure 2b). During this short period of time, our appreciation of autophagy’s role in renal physiology and disease pathogenesis has grown significantly. Early nephrology-related autophagy studies focused on the cytoprotective role of autophagy in renal tubular epithelial cells in the setting of acute kidney injury. In models of ischemia reperfusion injury, cisplatin-induced injury, and septic acute kidney injury, kidney injury was exacerbated when autophagy was inhibited using pharmacologic or genetic approaches.4 Augmenting autophagy is therefore Kidney International (2017) 91, 4–8
nephrology digest
Figure 1 | Schematic depiction of the autophagy pathway. Stressors, proinflammatory signals, and mechanistic target of rapamycin (mTOR) inhibition induce autophagy, leading to the nucleation of the phagosome membrane that surrounds cytoplasmic proteins and even whole organelles. Two conjugation systems serve to elongate the nucleation complex to form the limiting membrane. The forming limiting membrane sequesters cytosolic cargo and seals it to form an autophagosome that subsequently fuses with lysosomes in which cargo gets degraded followed by the release of nutrients to the cytosol. Autophagy can either mediate cell death or act as a prosurvival mechanism, depending on cellular contexts and stimuli. Reprinted from Schroppel B, Legendre C. Delayed graft function: from mechanism to translation. Kidney Int. 2014;86:251–258.8 Copyright ª 2014, with permission from Elsevier.
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Figure 2 | Kidney autophagy citations in PubMed. Histogram representing the total number of citations returned when searching with the term autophagy (a) and combined with kidney or renal (b). Kidney International (2017) 91, 4–8
5
nephrology digest
a promising candidate approach for preventing or treating acute kidney injury. The role of autophagy in chronic kidney disease is more complex and remains controversial.5 Two recent studies using the unilateral ureteral obstruction model in mice with proximal tubule-specific deletion of autophagyrelated genes illustrate the disparate results. Livingston et al.6 reported that conditional deletion of autophagy related 7 (ATG7) in proximal tubules ameliorated renal fibrosis after unilateral ureteral obstruction as did pharmacologic inhibition of autophagy with 3-methyladenine. Conversely, similar experiments in mice with conditional deletion of autophagy related 5 (ATG5) resulted in increased interstitial fibrosis, and rapamycin, a pharmacologic inducer of autophagy, reduced unilateral ureteral obstruction–induced renal fibrosis.7 These studies suggest that autophagy has an important role in mediating and/or modulating chronic kidney injury and fibrosis. However, further research is needed to identify the optimal context in which inducing or inhibiting autophagy might prevent progressive chronic kidney disease. Most studies on the role of autophagy in kidney disease have relied on pharmacologic agents that have “off-target” effects beyond inducing or inhibiting autophagy or on genetic knockouts of autophagy-related proteins that may have developmental effects. Future studies using drugs that are more specific for autophagy and animal models with inducible
modulation of autophagy before, during, or after kidney injury are needed to determine whether targeting autophagy is a viable approach for the prevention or treatment of kidney diseases. Although we have much to learn, one can envision a future in which autophagymodifying medications are used to prevent or treat kidney diseases. If realized, this future will only be possible because of the contributions of this year’s Nobel Prize winner for Physiology or Medicine, Yoshinori Ohsumi. DISCLOSURE All the authors declared no competing interests. REFERENCES 1. Takeshige K, Baba M, Tsuboi S, et al. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 1992;119:301–311. 2. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of. Saccharomyces cerevisiae. FEBS Lett. 1993;333:169–174. 3. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–662. 4. Kaushal GP, Shah SV. Autophagy in acute kidney injury. Kidney Int. 2016;89:779–791. 5. Lenoir O, Tharaux PL, Huber TB. Autophagy in kidney disease and aging: lessons from rodent models. Kidney Int. 2016;90:950–964. 6. Livingston MJ, Ding HF, Huang S, et al. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy. 2016;12:976–998. 7. Li H, Peng X, Wang Y, et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy. 2016;12: 1472–1486. 8. Schroppel B, Legendre C. Delayed graft function: from mechanism to translation. Kidney Int. 2014;86:251–258.
chronic kidney disease
A rose by any other name: is stage 3a chronic kidney disease really a disease? Christina M. Wyatt1 1 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence: Christina M. Wyatt, Division of Nephrology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1243, New York, New York 10029, USA. E-mail: christina.wyatt@mssm. edu
6
Experts have questioned the clinical relevance of early stage 3 chronic kidney disease, particularly in elderly individuals and in those without albuminuria. A recent study published in PLoS Medicine provides further evidence that many older adults with stage 3a chronic kidney disease will never worsen, whereas some may even improve. Despite limited generalizability, the results support the current, more nuanced classification of chronic kidney disease for use in clinical practice and in future epidemiologic research. Refers to: Shardlow A, McIntyre NJ, Fluck RJ, et al. Chronic kidney disease in primary care: outcomes after five years in a prospective cohort study. PLOS Med. 2016;13:e1002128. Kidney International (2017) 91, 6–8; http://dx.doi.org/10.1016/j.kint.2016.11.005 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Kidney International (2017) 91, 4–8