AMPK mediates regulation of glomerular volume and podocyte survival

Khadija Banu; Qisheng Lin; John M. Basgen; Marina Planoutene; Chengguo Wei; Anand C. Reghuvaran; Xuefei Tian; Hongmei Shi; Felipe Garzon; Aitor Garzia; Nicholas Chun; Arun Cumpelik; Andrew D. Santeusanio; Weijia Zhang; Bhaskar Das; Fadi Salem; Li Li; Shuta Ishibe; Lloyd G. Cantley; Lewis Kaufman; Kevin V. Lemley; Zhaohui Ni; John Cijiang He; Barbara Murphy; Madhav C. Menon

doi:10.1172/jci.insight.150004

AMPK mediates regulation of glomerular volume and podocyte survival

Khadija Banu, Qisheng Lin, John M. Basgen, Marina Planoutene, Chengguo Wei, Anand C. Reghuvaran, Xuefei Tian, Hongmei Shi, Felipe Garzon, Aitor Garzia, Nicholas Chun, Arun Cumpelik, Andrew D. Santeusanio, Weijia Zhang, Bhaskar Das, Fadi Salem, Li Li, Shuta Ishibe, Lloyd G. Cantley, Lewis KaufmanKevin V. Lemley, Zhaohui Ni, John Cijiang He, Barbara Murphy, Madhav C. Menon

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Abstract

Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

Original language	English (US)
Article number	e150004
Journal	JCI Insight
Volume	6
Issue number	19
DOIs	https://doi.org/10.1172/jci.insight.150004
State	Published - Oct 8 2021

Bibliographical note

Funding Information:
We acknowledge David Carling, University College London, London, United Kingdom, and Michael Caplan, Lloyd Cantley, and Shuta Ishibe of Yale University School of Medicine for critical discussions regarding data. We also acknowledge Peter Heeger of Mount Sinai for feedback on data, Gail Celio at the University of Minnesota Imaging Center, and Ronald Gordon at the electron microscopy core of Icahn School of Medicine at Mount Sinai. We would like to acknowledge Barbara Murphy for her strong support, encouragement, and mentorship, which were essential to the completion of this study. MCM wishes to acknowledge funding from the NIH (R01-DK122164), American Heart Association (AHASDG25870018), and philanthropy from Nina and Homer Eaton.NEPTUNE, U54-DK-083912, is a part of the NIH Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional funding and/or programmatic support for this project has been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation.

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Copyright: © 2021, Banu et al.

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Banu, K., Lin, Q., Basgen, J. M., Planoutene, M., Wei, C., Reghuvaran, A. C., Tian, X., Shi, H., Garzon, F., Garzia, A., Chun, N., Cumpelik, A., Santeusanio, A. D., Zhang, W., Das, B., Salem, F., Li, L., Ishibe, S., Cantley, L. G., ... Menon, M. C. (2021). AMPK mediates regulation of glomerular volume and podocyte survival. JCI Insight, 6(19), Article e150004. https://doi.org/10.1172/jci.insight.150004

Banu, K, Lin, Q, Basgen, JM, Planoutene, M, Wei, C, Reghuvaran, AC, Tian, X, Shi, H, Garzon, F, Garzia, A, Chun, N, Cumpelik, A, Santeusanio, AD, Zhang, W, Das, B, Salem, F, Li, L, Ishibe, S, Cantley, LG, Kaufman, L, Lemley, KV, Ni, Z, He, JC, Murphy, B & Menon, MC 2021, 'AMPK mediates regulation of glomerular volume and podocyte survival', JCI Insight, vol. 6, no. 19, e150004. https://doi.org/10.1172/jci.insight.150004

@article{20ebb95f95f1458b852536c5ad1c327c,

title = "AMPK mediates regulation of glomerular volume and podocyte survival",

abstract = "Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.",

author = "Khadija Banu and Qisheng Lin and Basgen, {John M.} and Marina Planoutene and Chengguo Wei and Reghuvaran, {Anand C.} and Xuefei Tian and Hongmei Shi and Felipe Garzon and Aitor Garzia and Nicholas Chun and Arun Cumpelik and Santeusanio, {Andrew D.} and Weijia Zhang and Bhaskar Das and Fadi Salem and Li Li and Shuta Ishibe and Cantley, {Lloyd G.} and Lewis Kaufman and Lemley, {Kevin V.} and Zhaohui Ni and He, {John Cijiang} and Barbara Murphy and Menon, {Madhav C.}",

note = "Funding Information: We acknowledge David Carling, University College London, London, United Kingdom, and Michael Caplan, Lloyd Cantley, and Shuta Ishibe of Yale University School of Medicine for critical discussions regarding data. We also acknowledge Peter Heeger of Mount Sinai for feedback on data, Gail Celio at the University of Minnesota Imaging Center, and Ronald Gordon at the electron microscopy core of Icahn School of Medicine at Mount Sinai. We would like to acknowledge Barbara Murphy for her strong support, encouragement, and mentorship, which were essential to the completion of this study. MCM wishes to acknowledge funding from the NIH (R01-DK122164), American Heart Association (AHASDG25870018), and philanthropy from Nina and Homer Eaton.NEPTUNE, U54-DK-083912, is a part of the NIH Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional funding and/or programmatic support for this project has been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. Publisher Copyright: Copyright: {\textcopyright} 2021, Banu et al.",

year = "2021",

month = oct,

day = "8",

doi = "10.1172/jci.insight.150004",

language = "English (US)",

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T1 - AMPK mediates regulation of glomerular volume and podocyte survival

AU - Banu, Khadija

AU - Lin, Qisheng

AU - Basgen, John M.

AU - Planoutene, Marina

AU - Wei, Chengguo

AU - Reghuvaran, Anand C.

AU - Tian, Xuefei

AU - Shi, Hongmei

AU - Garzon, Felipe

AU - Garzia, Aitor

AU - Chun, Nicholas

AU - Cumpelik, Arun

AU - Santeusanio, Andrew D.

AU - Zhang, Weijia

AU - Das, Bhaskar

AU - Salem, Fadi

AU - Li, Li

AU - Ishibe, Shuta

AU - Cantley, Lloyd G.

AU - Kaufman, Lewis

AU - Lemley, Kevin V.

AU - Ni, Zhaohui

AU - He, John Cijiang

AU - Murphy, Barbara

AU - Menon, Madhav C.

N1 - Funding Information: We acknowledge David Carling, University College London, London, United Kingdom, and Michael Caplan, Lloyd Cantley, and Shuta Ishibe of Yale University School of Medicine for critical discussions regarding data. We also acknowledge Peter Heeger of Mount Sinai for feedback on data, Gail Celio at the University of Minnesota Imaging Center, and Ronald Gordon at the electron microscopy core of Icahn School of Medicine at Mount Sinai. We would like to acknowledge Barbara Murphy for her strong support, encouragement, and mentorship, which were essential to the completion of this study. MCM wishes to acknowledge funding from the NIH (R01-DK122164), American Heart Association (AHASDG25870018), and philanthropy from Nina and Homer Eaton.NEPTUNE, U54-DK-083912, is a part of the NIH Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional funding and/or programmatic support for this project has been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. Publisher Copyright: Copyright: © 2021, Banu et al.

PY - 2021/10/8

Y1 - 2021/10/8

N2 - Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

AB - Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

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AMPK mediates regulation of glomerular volume and podocyte survival

Abstract

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UN SDGs

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AMPK mediates regulation of glomerular volume and podocyte survival

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

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University Imaging Centers

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