Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II-induced hypertension,Journal of Cellular Physiology

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Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II-induced hypertension
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-09-13 , DOI: 10.1002/jcp.30574
Changlong An ₁ , Baihai Jiao ₁ , Hao Du ₁ , Melanie Tran ₁ , Dong Zhou ₁ , Yanlin Wang _{1,

2,

3}

Affiliation

Hypertension is a major cause of chronic kidney disease. However, the pathogenesis of hypertensive kidney disease is not fully understood. Recently, we have shown that CXCL16/phosphoinositide-3 kinase γ (PI3Kγ) plays an important role in the development of renal inflammation and fibrosis in angiotensin II (AngII) induced hypertensive nephropathy. In the present study, we examined the role of phosphatase and tensin homolog (PTEN), a major regulator of PI3K signaling, in the pathogenesis of renal inflammation and fibrosis in an experimental model of hypertension induced by AngII. We generated myeloid PTEN conditional knockout mice by crossing PTEN^flox/flox mice with LysM-driven Cre mice. Littermate LysM-Cre⁻^/⁻PTEN^flox/flox mice were used as a control. Both myeloid PTEN knockout mice and their littermate control mice exhibited similar blood pressure at baseline. AngII treatment resulted in an increase in blood pressure that was comparable between myeloid PTEN knockout mice and littermate control mice. Compared with littermate control mice, myeloid PTEN knockout mice developed more severe kidney dysfunction, proteinuria, and fibrosis following AngII treatment. Furthermore, myeloid PTEN deficiency exacerbated total collagen deposition and extracellular matrix protein production and enhanced myeloid fibroblast accumulation and myofibroblast formation in the kidney following AngII treatment. Finally, myeloid PTEN deficiency markedly augmented infiltration of F4/80⁺ macrophages and CD3⁺ T cells into the kidneys of AngII-treated mice. Taken together, these results indicate that PTEN plays a crucial role in the pathogenesis of renal inflammation and fibrosis through the regulation of infiltration of myeloid fibroblasts, macrophages, and T lymphocytes into the kidney.

中文翻译：

骨髓 PTEN 缺乏会加重血管紧张素 II 诱导的高血压患者的肾脏炎症和纤维化

高血压是慢性肾病的主要原因。然而，高血压肾病的发病机制尚不完全清楚。最近，我们已经证明 CXCL16/磷酸肌醇 3 激酶 γ (PI3Kγ) 在血管紧张素 II (AngII) 诱导的高血压性肾病的肾脏炎症和纤维化的发展中起重要作用。在本研究中，我们在 AngII 诱导的高血压实验模型中检测了磷酸酶和张力蛋白同源物 (PTEN)（PI3K 信号传导的主要调节因子）在肾脏炎症和纤维化发病机制中的作用。^{我们通过将 PTEN flox/flox}小鼠与 LysM 驱动的 Cre 小鼠杂交来生成骨髓 PTEN 条件性敲除小鼠。同窝 LysM-Cre ^-^/^- PTEN ^flox/flox小鼠用作对照。骨髓 PTEN 敲除小鼠及其同窝对照小鼠在基线时表现出相似的血压。AngII 治疗导致血压升高，这在骨髓 PTEN 基因敲除小鼠和同窝对照小鼠之间是相当的。与同窝对照小鼠相比，骨髓 PTEN 敲除小鼠在 AngII 治疗后出现更严重的肾功能障碍、蛋白尿和纤维化。此外，骨髓 PTEN 缺乏加剧了总胶原蛋白沉积和细胞外基质蛋白的产生，并增强了 AngII 治疗后肾脏中的骨髓成纤维细胞积累和肌成纤维细胞形成。最后，骨髓 PTEN 缺乏显着增加了 F4/80 ⁺巨噬细胞和 CD3 ^+的浸润T 细胞进入 AngII 治疗小鼠的肾脏。总之，这些结果表明 PTEN 通过调节骨髓成纤维细胞、巨噬细胞和 T 淋巴细胞浸润到肾脏中，在肾脏炎症和纤维化的发病机制中起着至关重要的作用。

更新日期：2021-09-13

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