title: Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome.
abstract: Glucocorticoids are the primary therapy for nephrotic syndrome (NS), but have serious side effects and are ineffective in ~20-50% of patients. Thiazolidinediones have recently been suggested to be renoprotective, and to modulate podocyte glucocorticoid-mediated nuclear receptor signaling. We hypothesized that thiazolidinediones could enhance glucocorticoid efficacy in NS. We found that puromycin aminonucleoside-induced proteinuria in rats was significantly reduced by both high-dose glucocorticoids (79%) and pioglitazone (61%), but not low-dose glucocorticoids (25%). Remarkably, pioglitazone + low-dose glucocorticoids also reduced proteinuria (63%) comparably to high-dose glucocorticoids, whereas pioglitazone + high-dose glucocorticoids reduced proteinuria to almost control levels (97%). Molecular analysis revealed that both glucocorticoids and pioglitazone enhanced glomerular synaptopodin and nephrin expression, and reduced COX-2 expression, after injury. Furthermore, the glomerular phosphorylation of glucocorticoid receptor and Akt, but not PPARγ, correlated with treatment-induced reductions in proteinuria. Notably, clinical translation of these findings to a child with refractory NS by the addition of pioglitazone to the treatment correlated with marked reductions in both proteinuria (80%) and overall immunosuppression (64%). These findings together suggest that repurposing pioglitazone could potentially enhance the proteinuria-reducing effects of glucocorticoids during NS treatment.
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Chanley
authors.affiliation: James and Connie Maynard Children's Hospital, Greenville, NC, USA.
authors.forename: D
authors.initials: D
authors.lastname: Westbrook
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Nie
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kitao
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Guess
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Benndorf
authors.affiliation: James and Connie Maynard Children's Hospital, Greenville, NC, USA.|Department of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hidalgo
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Smoyer
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D003404:Creatinine / Q000652:urine; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D011507:Proteinuria / Q000209:etiology; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016482:Urinalysis
chemical_list: D005938:Glucocorticoids; D008565:Membrane Proteins; D008840:Microfilament Proteins; D047495:PPAR gamma; C503969:Synpo protein, rat; D045162:Thiazolidinediones; C113267:nephrin; D011692:Puromycin Aminonucleoside; D003404:Creatinine; D051546:Cyclooxygenase 2; D000077205:Pioglitazone