Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
The Einthoven Laboratory of Vascular and Regenerative Medicine, Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Int J Mol Sci. 2022 Aug 26;23(17):9660. doi: 10.3390/ijms23179660.
(1) Background: Soluble Fms-like tyrosine kinase 1 (sFLT1) is an endogenous VEGF inhibitor. sFLT1 has been described as an anti-inflammatory treatment for diabetic nephropathy and heart fibrosis. However, sFLT1 has also been related to peritubular capillary (PTC) loss, which promotes fibrogenesis. Here, we studied whether transfection with aggravates experimental AKI-to-CKD transition and whether sFLT1 is increased in human kidney fibrosis. (2) Methods: Mice were transfected via electroporation with . After confirming transfection efficacy, mice underwent unilateral ischemia/reperfusion injury (IRI) and were sacrificed 28 days later. Kidney histology and RNA were analyzed to study renal fibrosis, PTC damage and inflammation. Renal sFLT1 mRNA expression was measured in CKD biopsies and control kidney tissue. (3) Results: transfection did not aggravate renal fibrosis, PTC loss or macrophage recruitment in IRI mice. In contrast, higher transfection efficiency was correlated with reduced expression of pro-fibrotic and pro-inflammatory markers. In the human samples, sFLT1 mRNA levels were similar in CKD and control kidneys and were not correlated with interstitial fibrosis or PTC loss. (4) Conclusion: As we previously found that sFLT1 has therapeutic potential in diabetic nephropathy, our findings indicate that sFLT1 can be administered at a dose that is therapeutically effective in reducing inflammation, without promoting maladaptive kidney damage.
(1) 背景：可溶性 fms 样酪氨酸激酶 1（sFLT1）是一种内源性 VEGF 抑制剂。sFLT1 已被描述为治疗糖尿病肾病和心脏纤维化的抗炎治疗方法。然而，sFLT1 也与肾小管周毛细血管（PTC）丧失有关，后者促进了纤维化的发生。在这里，我们研究了转染 sFLT1 是否会加重实验性 AKI 向 CKD 的转变，以及 sFLT1 是否在人类肾脏纤维化中增加。(2) 方法：通过电穿孔将小鼠转染 。在确认转染效果后，对小鼠进行单侧缺血/再灌注损伤（IRI），28 天后处死。分析肾脏组织学和 RNA 以研究肾纤维化、PTC 损伤和炎症。在 CKD 活检和对照肾脏组织中测量肾脏 sFLT1 mRNA 表达。(3) 结果：转染 不会加重 IRI 小鼠的肾纤维化、PTC 丢失或巨噬细胞募集。相反，更高的转染效率与减少促纤维化和促炎标志物的表达相关。在人类样本中，sFLT1 mRNA 水平在 CKD 和对照肾脏中相似，与间质纤维化或 PTC 丢失无关。(4) 结论：正如我们之前发现 sFLT1 在糖尿病肾病中有治疗潜力一样，我们的发现表明，sFLT1 可以以治疗有效剂量给药，以减少炎症，而不会促进适应性肾脏损伤。
