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
Affiliations
Claire Bryant
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
Galen Rask
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
Amanda P. Waller
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
Amy Webb
The Ohio State University, Department of Biomedical Informatics, Columbus, OH, USA
Marina R. Galdino-Pitta
Laboratory of Design and Drug Synthesis, Bioscience Center, Federal University of Pernambuco, Recife, Brazil
Angelica A. Amato
Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil
Rachel Cianciolo
Deptartment of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
Rajgopal Govindarajan
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
Brian Becknell
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
Bryce A. Kerlin
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
Francisco A.R. Neves
Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil
Alessia Fornoni
Katz Family Division of Nephrology and Hypertension, Peggy and Harold Katz Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL, USA
Shipra Agrawal
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA; Corresponding author
Summary: 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.
