Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome.
Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome.
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DOI：
10.1016/j.isci.2022.104001
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发表时间：
2022-04-15
期刊：
影响因子：
5.8
通讯作者：
Agrawal S
中科院分区：
文献类型：
--
作者：
Bryant C;Rask G;Waller AP;Webb A;Galdino-Pitta MR;Amato AA;Cianciolo R;Govindarajan R;Becknell B;Kerlin BA;Neves FAR;Fornoni A;Agrawal S
肾小球疾病表现为肾病综合征（NS），伴有高蛋白尿和合并症，并且通常对标准治疗无效。我们假设 PPARγ 的选择性调节剂 GQ-16 将为 NS 治疗提供优于传统 PPARγ 激动剂的治疗优势。我们在临床前 NS 模型中证明，与对照组相比，吡格列酮可将蛋白尿降低至 64%，而 GQ-16 可将肾病蛋白尿显着降低至 81%。尽管 GQ-16 和吡格列酮均可恢复肾小球 Nphs1、肝脏 Pcsk9 和血清胆固醇，但只有 GQ-16 可以恢复肾小球 Nrf2，并减少低白蛋白血症和高凝血症。通过 RNA-seq 分析，GQ-16 和吡格列酮可恢复常见且独特的肾小球基因表达，并不同程度地诱导胰岛素增敏脂肪因子。吡格列酮而非 GQ-16 会诱导脂肪细胞和白色脂肪组织中更多的脂质积累和 aP2。我们得出的结论是，通过部分激动剂 GQ-16 选择性调节 PPARγ 在减少蛋白尿、NS 相关合并症和完全 PPARγ 激动剂的脂肪生成副作用方面比吡格列酮更有利。选择性调节 PPARγ 在 NS 中提供优于完全激动的治疗优势 GQ-16 通过高效 RNA-Seq 减少 NS 中的蛋白尿和相关合并症，通过 GQ-16 和吡格列酮鉴定出常见和独特的肾小球基因表达 吡格列酮诱导更多的脂肪生成标志物，GQ-16 在更大程度上诱导脂肪因子分子生理学；细胞生物学
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. Selective Modulation of PPARγ offers therapeutic advantage over full agonism in NS GQ-16 reduces proteinuria in NS and associated comorbidities with high efficacy RNA-Seq identified common and distinct glomerular gene expression by GQ-16 and pioglitazone Pioglitazone induces more markers of adipogenesis, and GQ-16 induces adipokines to a greater degree Nephrology; Molecular physiology; Cell biology
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
de Jonge HJ;Fehrmann RS;de Bont ES;Hofstra RM;Gerbens F;Kamps WA;de Vries EG;van der Zee AG;te Meerman GJ;ter Elst A
通讯作者：
ter Elst A
影响因子：
29
作者：
Hall JA;Ramachandran D;Roh HC;DiSpirito JR;Belchior T;Zushin PH;Palmer C;Hong S;Mina AI;Liu B;Deng Z;Aryal P;Jacobs C;Tenen D;Brown CW;Charles JF;Shulman GI;Kahn BB;Tsai LTY;Rosen ED;Spiegelman BM;Banks AS
通讯作者：
Banks AS
影响因子：
7.5
作者：
Almeida-Oliveira, Fernanda;Leandro, Joao G. B.;Majerowicz, David
通讯作者：
Majerowicz, David
影响因子：
19.6
作者：
Floege, Juergen;Barbour, Sean J.;Wenderfer, Scott E.
通讯作者：
Wenderfer, Scott E.