iScience (Apr 2022)

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

Journal volume & issue
Vol. 25, no. 4
p. 104001

Abstract

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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.

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