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    Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome

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    Author
    Agrawal, S; Chanley, M; Westbrook, D; Nie, X; Kiato, T; Guess, A; Benndorf, R.; Hidalgo, G; Smoyer, W
    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.
    URI
    http://hdl.handle.net/10342/7962
    Date
    2016-05
    Citation:
    APA:
    Agrawal, S, & Chanley, M, & Westbrook, D, & Nie, X, & Kiato, T, & Guess, A, & Benndorf, R., & Hidalgo, G, & Smoyer, W. (May 2016). Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome. Scientific Reports, (6:1), p.. Retrieved from http://hdl.handle.net/10342/7962

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    MLA:
    Agrawal, S, and Chanley, M, and Westbrook, D, and Nie, X, and Kiato, T, and Guess, A, and Benndorf, R., and Hidalgo, G, and Smoyer, W. "Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome". Scientific Reports. 6:1. (.), May 2016. February 27, 2021. http://hdl.handle.net/10342/7962.
    Chicago:
    Agrawal, S and Chanley, M and Westbrook, D and Nie, X and Kiato, T and Guess, A and Benndorf, R. and Hidalgo, G and Smoyer, W, "Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome," Scientific Reports 6, no. 1 (May 2016), http://hdl.handle.net/10342/7962 (accessed February 27, 2021).
    AMA:
    Agrawal, S, Chanley, M, Westbrook, D, Nie, X, Kiato, T, Guess, A, Benndorf, R., Hidalgo, G, Smoyer, W. Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome. Scientific Reports. May 2016; 6(1) . http://hdl.handle.net/10342/7962. Accessed February 27, 2021.
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