He Mingjuan, Li Yixiang, Wang Li, Guo Bei, Mei Wen, Zhu Biao, Zhang Jiajia, Ding Yan, Meng Biying, Zhang Liming, Xiang Lin, Dong Jing, Liu Min, Xiang Lingwei, Xiang Guangda
The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China.
Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan, 430070, Hubei Province, China.
Diabetologia. 2020 Sep;63(9):1916-1931. doi: 10.1007/s00125-020-05197-2. Epub 2020 Jun 25.
AIMS/HYPOTHESIS: Myeloid-derived growth factor (MYDGF), mainly secreted by bone marrow-derived cells, has been known to promote glucagon-like peptide-1 production and improve glucose/lipid metabolism in mouse models of diabetes, but little is known about the functions of MYDGF in diabetic kidney disease (DKD). Here, we investigated whether MYDGF can prevent the progression of DKD.
In vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of MYDGF on albuminuria and pathological glomerular lesions. We used streptozotocin-treated Mydgf knockout and wild-type mice on high fat diets to induce a model of DKD. Then, albuminuria, glomerular lesions and podocyte injury were evaluated in Mydgf knockout and wild-type DKD mice treated with adeno-associated virus-mediated Mydgf gene transfer. In vitro and ex vivo experiments, the expression of slit diaphragm protein nephrin and podocyte apoptosis were evaluated in conditionally immortalised mouse podocytes and isolated glomeruli from non-diabetic wild-type mice treated with recombinant MYDGF.
MYDGF deficiency caused more severe podocyte injury in DKD mice, including the disruption of slit diaphragm proteins (nephrin and podocin) and an increase in desmin expression and podocyte apoptosis, and subsequently caused more severe glomerular injury and increased albuminuria by 39.6% compared with those of wild-type DKD mice (p < 0.01). Inversely, MYDGF replenishment attenuated podocyte and glomerular injury in both wild-type and Mydgf knockout DKD mice and then decreased albuminuria by 36.7% in wild-type DKD mice (p < 0.01) and 34.9% in Mydgf knockout DKD mice (p < 0.01). Moreover, recombinant MYDGF preserved nephrin expression and inhibited podocyte apoptosis in vitro and ex vivo. Mechanistically, the renoprotection of MYDGF was attributed to the activation of the Akt/Bcl-2-associated death promoter (BAD) pathway.
CONCLUSIONS/INTERPRETATION: The study demonstrates that MYDGF protects podocytes from injury and prevents the progression of DKD, providing a novel strategy for the treatment of DKD. Graphical abstract.
目的/假设：髓系来源生长因子（MYDGF）主要由骨髓来源细胞分泌，已知其在糖尿病小鼠模型中可促进胰高血糖素样肽-1的产生并改善糖脂代谢，但MYDGF在糖尿病肾病（DKD）中的功能鲜为人知。在此，我们研究了MYDGF是否能预防DKD的进展。
在体内实验中，采用功能缺失和功能获得策略来评估MYDGF对蛋白尿和肾小球病理损伤的影响。我们使用链脲佐菌素处理的Mydgf基因敲除和野生型小鼠，给予高脂饮食以诱导DKD模型。然后，在接受腺相关病毒介导的Mydgf基因转移治疗的Mydgf基因敲除和野生型DKD小鼠中评估蛋白尿、肾小球损伤和足细胞损伤。在体外和离体实验中，在条件永生化小鼠足细胞和从非糖尿病野生型小鼠分离的肾小球中，用重组MYDGF处理后评估裂孔隔膜蛋白nephrin的表达和足细胞凋亡。
MYDGF缺乏导致DKD小鼠中更严重的足细胞损伤，包括裂孔隔膜蛋白（nephrin和podocin）的破坏、结蛋白表达增加和足细胞凋亡增加，随后导致比野生型DKD小鼠更严重的肾小球损伤，蛋白尿增加39.6%（p<0.01）。相反，补充MYDGF可减轻野生型和Mydgf基因敲除DKD小鼠的足细胞和肾小球损伤，然后使野生型DKD小鼠的蛋白尿减少36.7%（p<0.01），Mydgf基因敲除DKD小鼠的蛋白尿减少34.9%（p<0.01）。此外，重组MYDGF在体外和离体实验中均可保留nephrin表达并抑制足细胞凋亡。从机制上讲，MYDGF的肾脏保护作用归因于Akt/Bcl-2相关死亡促进因子（BAD）途径的激活。
结论/解读：该研究表明，MYDGF可保护足细胞免受损伤并预防DKD的进展，为DKD的治疗提供了一种新策略。图形摘要。
