Inflammation Is More Sensitive than Cell Proliferation in Response to Rapamycin Treatment in Polycystic Kidney Disease.

IF 2.3 4区医学 Q2 PERIPHERAL VASCULAR DISEASE Kidney & blood pressure research Pub Date : 2024-01-01 Epub Date: 2024-01-02 DOI:10.1159/000535750

Ming Yang, Jiayi Lv, Chanjuan Gong, Cheng Xue, Lili Fu, Shunjie Chen, Changlin Mei

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Abstract

Introduction: It has been reported that rapamycin inhibited inflammation in renal interstitial diseases. We therefore hypothesized that rapamycin could attenuate inflammation in polycystic kidney disease (PKD).

Methods: Han:SPRD rats were treated with rapamycin by daily gavage from 4 weeks to 12 weeks of age at the dosage of 0.5 mg/kg/day (low dose) or 1 mg/kg/day (high dose). WT9-12 human PKD cells were treated with various concentrations of rapamycin.

Results: Two-kidney/total body weight ratio and cystic index in Cy/+ kidneys were significantly reduced with the treatment of low-dose rapamycin and further reduced by the treatment with high-dose rapamycin. However, the renal function of Cy/+ rats was equally improved by the treatment with either low-dose or high-dose rapamycin. The renal cell proliferation was significantly decreased in Cy/+ kidneys with the treatment of low-dose rapamycin and was further decreased with the treatment of high-dose rapamycin as examined by Ki67 staining. The phosphorylation of S6K in cystic kidneys was decreased by low-dose rapamycin and further decreased by high-dose rapamycin. Both low-dose and high-dose rapamycin treatment decreased macrophage infiltration and the expression of complement factor B (CFB), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) to a similar level. The expression of CFB, MCP-1, and TNF-α and phosphorylation of S6K were inhibited in WT9-12 cells treated with 10 nm rapamycin at 24 h and 48 h, respectively. Moreover, the phosphorylation of Akt was not increased by 1 nm and 10 nm of rapamycin and enhanced by 1 μm rapamycin treatment. Interestingly, WT9-12 cell proliferation could be inhibited by 1 μm rapamycin.

Conclusion: Low dose of rapamycin could inhibit inflammation and protect renal function in PKD. Inflammation is more sensitive than cell proliferation in response to rapamycin treatment in PKD.

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在多囊肾病中，炎症比细胞增殖对雷帕霉素治疗的反应更敏感。

前言据报道，雷帕霉素可抑制肾间质疾病的炎症反应。方法：从 4 周龄至 12 周龄的 SPRD 大鼠每天灌胃雷帕霉素，剂量为 0.5mg/kg/day （低剂量）或 1mg/kg/day （高剂量）。用不同浓度的雷帕霉素处理WT9-12人PKD细胞：结果：低剂量雷帕霉素治疗后，Cy/+肾脏的双肾/总重量比和囊性指数显著降低，高剂量雷帕霉素治疗后进一步降低。然而，使用小剂量或大剂量雷帕霉素治疗后，Cy/+大鼠的肾功能同样得到了改善。通过 Ki-67 染色法检测，低剂量雷帕霉素治疗后 Cy/+ 肾脏的肾细胞增殖明显减少，而高剂量雷帕霉素治疗后则进一步减少。小剂量雷帕霉素可减少囊肿肾中S6K的磷酸化，大剂量雷帕霉素可进一步减少其磷酸化。小剂量和大剂量雷帕霉素治疗均可减少巨噬细胞浸润，并降低CFB、MCP-1和TNF-α的表达至相似水平。用 10 nM 雷帕霉素处理 WT9-12 细胞 24 小时和 48 小时后，CFB、MCP-1 和 TNF-α 的表达以及 S6K 的磷酸化分别受到抑制。此外，1 nM 和 10 nM 的雷帕霉素不会增加 Akt 的磷酸化，而 1 μM 的雷帕霉素会增强 Akt 的磷酸化。有趣的是，1 μM雷帕霉素可抑制WT9-12细胞的增殖：结论：小剂量雷帕霉素可抑制炎症，保护PKD患者的肾功能。炎症比细胞增殖对雷帕霉素治疗更敏感。

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来源期刊

Kidney & blood pressure research 医学-泌尿学与肾脏学

CiteScore

4.80

自引率

3.60%

发文量

审稿时长

6-12 weeks

期刊介绍： This journal comprises both clinical and basic studies at the interface of nephrology, hypertension and cardiovascular research. The topics to be covered include the structural organization and biochemistry of the normal and diseased kidney, the molecular biology of transporters, the physiology and pathophysiology of glomerular filtration and tubular transport, endothelial and vascular smooth muscle cell function and blood pressure control, as well as water, electrolyte and mineral metabolism. Also discussed are the (patho)physiology and (patho) biochemistry of renal hormones, the molecular biology, genetics and clinical course of renal disease and hypertension, the renal elimination, action and clinical use of drugs, as well as dialysis and transplantation. Featuring peer-reviewed original papers, editorials translating basic science into patient-oriented research and disease, in depth reviews, and regular special topic sections, ''Kidney & Blood Pressure Research'' is an important source of information for researchers in nephrology and cardiovascular medicine.