Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome

Claire Bryant; Galen Rask; Amanda P. Waller; Amy Webb; Marina R. Galdino-Pitta; Angelica A. Amato; Rachel Cianciolo; Rajgopal Govindarajan; Brian Becknell; Bryce A. Kerlin; Francisco A.R. Neves; Alessia Fornoni; Shipra Agrawal

doi:10.1016/j.isci.2022.104001

Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome

Claire Bryant, Galen Rask, Amanda P. Waller, Amy Webb, Marina R. Galdino-Pitta, Angelica A. Amato, Rachel Cianciolo, Rajgopal Govindarajan, Brian Becknell, Bryce A. Kerlin, Francisco A.R. Neves, Alessia Fornoni, Shipra Agrawal

Research output: Contribution to journal › Article › peer-review

Abstract

Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.

Original language	English (US)
Article number	104001
Journal	iScience
Volume	25
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2022.104001
State	Published - Apr 15 2022
Externally published	Yes

Keywords

Cell biology
Molecular physiology
Nephrology

ASJC Scopus subject areas

General

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10.1016/j.isci.2022.104001

Cite this

Bryant, C., Rask, G., Waller, A. P., Webb, A., Galdino-Pitta, M. R., Amato, A. A., Cianciolo, R., Govindarajan, R., Becknell, B., Kerlin, B. A., Neves, F. A. R., Fornoni, A., & Agrawal, S. (2022). Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome. iScience, 25(4), [104001]. https://doi.org/10.1016/j.isci.2022.104001

Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome. / Bryant, Claire; Rask, Galen; Waller, Amanda P.; Webb, Amy; Galdino-Pitta, Marina R.; Amato, Angelica A.; Cianciolo, Rachel; Govindarajan, Rajgopal; Becknell, Brian; Kerlin, Bryce A.; Neves, Francisco A.R.; Fornoni, Alessia; Agrawal, Shipra.

In: iScience, Vol. 25, No. 4, 104001, 15.04.2022.

Research output: Contribution to journal › Article › peer-review

Bryant, C, Rask, G, Waller, AP, Webb, A, Galdino-Pitta, MR, Amato, AA, Cianciolo, R, Govindarajan, R, Becknell, B, Kerlin, BA, Neves, FAR, Fornoni, A & Agrawal, S 2022, 'Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome', iScience, vol. 25, no. 4, 104001. https://doi.org/10.1016/j.isci.2022.104001

Bryant, Claire ; Rask, Galen ; Waller, Amanda P. ; Webb, Amy ; Galdino-Pitta, Marina R. ; Amato, Angelica A. ; Cianciolo, Rachel ; Govindarajan, Rajgopal ; Becknell, Brian ; Kerlin, Bryce A. ; Neves, Francisco A.R. ; Fornoni, Alessia ; Agrawal, Shipra. / Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome. In: iScience. 2022 ; Vol. 25, No. 4.

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title = "Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome",

abstract = "Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.",

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author = "Claire Bryant and Galen Rask and Waller, {Amanda P.} and Amy Webb and Galdino-Pitta, {Marina R.} and Amato, {Angelica A.} and Rachel Cianciolo and Rajgopal Govindarajan and Brian Becknell and Kerlin, {Bryce A.} and Neves, {Francisco A.R.} and Alessia Fornoni and Shipra Agrawal",

note = "Funding Information: We thank Jeffrey Miner, Washington University, St Louis, Missouri for his valuable comments and suggestions and for his mentorship on the American Heart Association Career Development Award granted to SA. We also thank Alexander S Banks, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA for critical comments and review of the manuscript. We thank the Genomics Core Resources at The Ohio State University for RNA Sequencing Services. This study was supported by the American Heart Association Career Development Award (CDA34110287) and funds from Nationwide Children's Hospital, United States to SA. The project described was also funded by the Center for Clinical and Translational Science Genomics Shared Resource Voucher Support to SA which was supported by the NIH Clinical and Translational Science Award to The Ohio State University (Award Number UL1TR002733) from the National Center for Advancing Translational Sciences, United States. CB performed experiments, analyzed and interpreted the data, prepared figures and tables, and drafted the manuscript. GR, APW, and AAA performed experiments and edited the manuscript. BAK and APW interpreted the coagulopathy data and edited the manuscript. RC performed the histological analysis and edited the manuscript. MRG synthesized and provided the compound GQ-16 for these studies and edited the manuscript. AW performed bioinformatics analysis and edited the manuscript. FARN, BB, RG and AF interpreted the data and edited the manuscript. SA conceptualized and designed the study, analyzed and interpreted the data, prepared figures and tables, and drafted and edited the manuscript. All the authors approve of the final version of the manuscript. Part of these findings were selected for Platform Presentation at the 13th International Podocyte Conference, held virtually at the University of Manchester, July 27?31, 2021 and at the ASN-APS Emerging Kidney Scientist Seminar Series, held virtually on Nov 1, 2021. The authors declare no competing interests. An Intellectual Property Application for international patent (#63/016,039) ?PPAR Agonists for Treatment of Kidney Disease? has been filed by SA and the Office of Technology Commercialization at Nationwide Children's Hospital. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: We thank Jeffrey Miner, Washington University, St Louis, Missouri for his valuable comments and suggestions and for his mentorship on the American Heart Association Career Development Award granted to SA. We also thank Alexander S Banks, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA for critical comments and review of the manuscript. We thank the Genomics Core Resources at The Ohio State University for RNA Sequencing Services. This study was supported by the American Heart Association Career Development Award ( CDA34110287 ) and funds from Nationwide Children's Hospital, United States to SA. The project described was also funded by the Center for Clinical and Translational Science Genomics Shared Resource Voucher Support to SA which was supported by the NIH Clinical and Translational Science Award to The Ohio State University (Award Number UL1TR002733 ) from the National Center for Advancing Translational Sciences, United States . Publisher Copyright: {\textcopyright} 2022 The Authors",

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doi = "10.1016/j.isci.2022.104001",

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T1 - Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome

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AU - Rask, Galen

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AU - Webb, Amy

AU - Galdino-Pitta, Marina R.

AU - Amato, Angelica A.

AU - Cianciolo, Rachel

AU - Govindarajan, Rajgopal

AU - Becknell, Brian

AU - Kerlin, Bryce A.

AU - Neves, Francisco A.R.

AU - Fornoni, Alessia

AU - Agrawal, Shipra

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N2 - Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.

AB - Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.

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Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome

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