Clinic of Nephrology and Rheumatology, University Hospital of Göttingen , Göttingen , Germany.
Department of Nephrology, University Hospital Essen, University Duisburg-Essen , Essen , Germany.
Am J Physiol Renal Physiol. 2018 Oct 1;315(4):F1139-F1148. doi: 10.1152/ajprenal.00502.2017. Epub 2018 Jun 13.
Acute kidney injury (AKI) occurs frequently in hospitals worldwide, but the therapeutic options are limited. Diabetes mellitus (DM) affects more and more people around the globe. The disease worsens the prognosis of AKI even further. In recent years, cell-based therapies have increasingly been applied in experimental AKI. The aim of the study was to utilize two established autophagy inducers for pharmacological preconditioning of so-called proangiogenic cells (PACs) in PAC treatment of diabetic AKI. Insulin-dependent DM was induced in male C57/Bl6N mice by intraperitoneal injections of streptozotocine. Six weeks later, animals underwent bilateral renal ischemia for 45 min, followed by intravenous injections of either native or zVAD (benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone)- or Z-Leu-Leu-Leu-al (MG132)-pretreated syngeneic murine PACs. Mice were analyzed 48 h (short term) and 6 wk (long term) later, respectively. DM worsened postischemic AKI, and PAC preconditioning with zVAD and MG132 resulted in a further decline of excretory kidney function. Injection of native PACs reduced fibrosis in nondiabetic mice, but cell preconditioning promoted interstitial matrix accumulation significantly. Both substances aggravated endothelial-to-mesenchymal transition (EndoMT) under diabetic conditions; these effects occurred either exclusively in the short (zVAD) or in the short and long term (MG132). Preconditioned cells stimulated the autophagocytic flux in intrarenal endothelial cells, and all experimental groups displayed increased endothelial abundances of senescence-associated β-galactosidase, a marker of premature cell senescence. Pharmacological autophagy activation may not serve as an effective strategy for improving PAC competence in diabetic AKI in general. On the contrary, several outcome parameters (excretory function, fibrosis, EndoMT) may even be worsened.
急性肾损伤 (AKI) 在全球范围内的医院中频繁发生，但治疗选择有限。糖尿病 (DM) 影响着全球越来越多的人。该疾病进一步恶化了 AKI 的预后。近年来，细胞治疗在实验性 AKI 中得到了越来越多的应用。本研究的目的是利用两种已建立的自噬诱导剂对所谓的促血管生成细胞 (PAC) 进行药理学预处理，以治疗糖尿病性 AKI。通过腹腔注射链脲佐菌素诱导雄性 C57/Bl6N 小鼠产生胰岛素依赖性 DM。6 周后，动物进行双侧肾缺血 45 分钟，随后静脉注射未预处理或 zVAD（苯甲氧基羰基-Val-Ala-Asp-氟甲基酮）或 Z-Leu-Leu-Leu-al（MG132）预处理的同种异体鼠 PAC。分别在 48 小时（短期）和 6 周（长期）后分析小鼠。DM 加重了缺血后 AKI，zVAD 和 MG132 预处理的 PAC 导致排泄肾功能进一步下降。在非糖尿病小鼠中，注射天然 PAC 可减少纤维化，但细胞预处理会显著促进间质基质积累。两种物质在糖尿病条件下均加剧内皮-间充质转化 (EndoMT)；这些作用仅在短期（zVAD）或短期和长期（MG132）发生。预处理细胞刺激了肾内内皮细胞的自噬流，所有实验组的内皮细胞中衰老相关β-半乳糖苷酶（细胞衰老的标志物）的丰度均增加。药理学自噬激活可能不适用于一般改善糖尿病性 AKI 中 PAC 功能的有效策略。相反，一些结局参数（排泄功能、纤维化、EndoMT）甚至可能恶化。
