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 journalArticlepeer-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 languageEnglish (US)
Article number104001
JournaliScience
Volume25
Issue number4
DOIs
StatePublished - Apr 15 2022
Externally publishedYes

Keywords

  • Cell biology
  • Molecular physiology
  • Nephrology

ASJC Scopus subject areas

  • General

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