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

iScience. 2022 Feb 28;25(4):104001. doi: 10.1016/j.isci.2022.104001. eCollection 2022 Apr 15.

Authors

Claire Bryant¹, Galen Rask¹, Amanda P Waller¹, Amy Webb², Marina R Galdino-Pitta³, Angelica A Amato⁴, Rachel Cianciolo⁵, Rajgopal Govindarajan⁶, Brian Becknell^{1

7}, Bryce A Kerlin^{1

7}, Francisco A R Neves⁴, Alessia Fornoni⁸, Shipra Agrawal^{1

7}

Affiliations

¹ Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
² The Ohio State University, Department of Biomedical Informatics, Columbus, OH, USA.
³ Laboratory of Design and Drug Synthesis, Bioscience Center, Federal University of Pernambuco, Recife, Brazil.
⁴ Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil.
⁵ Deptartment of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
⁶ Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
⁷ Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.
⁸ Katz Family Division of Nephrology and Hypertension, Peggy and Harold Katz Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL, USA.

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.

Keywords: Cell biology; Molecular physiology; Nephrology.

Abstract

Grants and funding