Pioglitazone enhances proteinuria reduction in complicated pediatric nephrotic syndrome

Hunley, Tracy E.; Hidalgo, Guillermo; Ng, Kar Hui; Shirai, Yoko; Miura, Kenichiro; Beng, Hostensia; Wu, Qiang; Hattori, Motoshi; Smoyer, William E.

doi:10.1007/s00467-022-05637-8

Cited by 4 publications

(1 citation statement)

References 35 publications

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“…This suggested the potential clinical use of these FDA-approved drugs in enabling the reduction of steroid dose, toxicity, and side effects to treat NS. We further translated these findings and demonstrated the ability of pioglitazone administration to improve clinical outcome in a child with steroid-refractory NS, which has now been extended in other NS patients as well [ 6 , 65 ]. Moreover, we have recently found that targeting PPARγ with a selective modulator, GQ-16, offers an even better therapeutic strategy in NS, by reducing proteinuria and NS-associated side effects with a greater efficacy while providing reduced adipogenic effects than traditional TZDs [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue

Bryant

Webb

Banks

et al. 2022

Cells

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Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPARγ activation. This indicates a pivotal role for PPARγ in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPARγ signaling remains limited. We performed a comprehensive analysis of PPARγ mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPARγ Var 1 (encoding γ1) and not Var2 (encoding γ2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs. adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPARγ1 variant, distinct from the adipocyte-specific γ2 variant. In summary, podocytes and glomeruli express several PPARγ variants, including Var1 (γ1) and excluding adipocyte-specific Var2 (γ2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that that new selective PPARγ modulators can be potentially developed that will be able to distinguish between the two forms, γ1 and γ2, thus forming a basis of novel targeted therapeutic avenues.

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Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue

Bryant

Webb

Banks

et al. 2022

Cells

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Pioglitazone, a PPAR-y agonist, as one of the new therapeutic candidates for C3 glomerulopathy

Balestra¹,

Barbi²,

Ceconi³

et al. 2023

Pediatr Nephrol

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Background C3-glomerulopathy (C3G) is a rare pediatric kidney disease characterised by dysregulation of the alternative complement pathway, with glomerular deposition of C3. C3G may often present as a steroid-resistant nephrotic syndrome (SRNS), and there is no established effective therapy: the usual treatment involves corticosteroids and immunosuppressive drugs. Pioglitazone, a PPAR-γ agonist with a protective action on podocytes, was reported in a few cases as helpful in reducing proteinuria when combined with steroids. Case-Diagnosis/Treatment We report the case of a 13-year-old girl with silent past medical history who presented with SRNS. A kidney biopsy showed findings indicative of C3G. A low sodium diet and angiotensin-converting enzyme inhibitor were started; immunosuppressive treatment with mycophenolate mofetil (MMF) was administered due to the cortico-resistance. Because of poor response to the immunosuppressant, a trial with eculizumab was attempted without significant response and persistence of proteinuria in the nephrotic range. A further therapeutic trial was performed with tacrolimus with no disease remission. Due to a severe deterioration in her condition, the girl was hospitalized and treated with high-dose steroid bolus. A daily dose of oral prednisone and MMF were re-started without benefit with persistent levels of nephrotic range proteinuria. The administration of pioglitazone consistently lowered proteinuria levels for the first time since the onset of the disease, with a maintenance of the effect and normalization (< 0.15 g/24 h) at the 10-month follow-up. Conclusions In this patient affected by C3G, pioglitazone proved effective in reducing proteinuria levels.

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Multiple drugs

2023

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Pioglitazone enhances proteinuria reduction in complicated pediatric nephrotic syndrome

Cited by 4 publications

References 35 publications

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue

Pioglitazone, a PPAR-y agonist, as one of the new therapeutic candidates for C3 glomerulopathy

Multiple drugs

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