Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome

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 hypothes...

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Bibliographic Details
Published in:	Scientific reports Vol. 6; no. 1; p. 24392
Main Authors:	Agrawal, S., Chanley, M. A., Westbrook, D., Nie, X., Kitao, T., Guess, A. J., Benndorf, R., Hidalgo, G., Smoyer, W. E.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-05-2016 Nature Publishing Group
Subjects:	14 14/63 631/1647/334 631/337/505 631/80 692/4022/1585/2759 82 82/1 82/29 82/80 96 AKT protein Albuminuria - etiology Animals Creatinine - urine Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Cyclooxygenase-2 Drug Therapy, Combination Glucocorticoids Glucocorticoids - adverse effects Glucocorticoids - pharmacology Glucocorticoids - therapeutic use Humanities and Social Sciences Immunosuppression Kidney diseases Kidney Glomerulus - drug effects Kidney Glomerulus - metabolism Kidney Glomerulus - pathology Male Membrane Proteins - genetics Membrane Proteins - metabolism Microfilament Proteins - genetics Microfilament Proteins - metabolism multidisciplinary Nephrotic syndrome Nephrotic Syndrome - chemically induced Nephrotic Syndrome - drug therapy Nephrotic Syndrome - pathology Phosphorylation Phosphorylation - drug effects Pioglitazone PPAR gamma - metabolism Proteinuria Proteinuria - etiology Puromycin Puromycin Aminonucleoside - toxicity Rats Rats, Wistar Rodents Science Side effects Signal Transduction - drug effects Thiazolidinediones Thiazolidinediones - pharmacology Thiazolidinediones - therapeutic use Urinalysis
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/srep24392