Mingjuan He1,2,3, Yixiang Li4, Li Wang1,2, Bei Guo1,2, Wen Mei2, Biao Zhu2, Jiajia Zhang2, Yan Ding1,2, Biying Meng1,2, Liming Zhang1,2, Lin Xiang2, Jing Dong2, Min Liu2, Lingwei Xiang5, Guangda Xiang6,7. 1. The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China. 2. Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan, 430070, Hubei Province, China. 3. Department of Endocrinology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. 4. Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, USA. 5. ICF, 2635 Century Pkwy NE Unit 1000, Atlanta, GA, 30345, USA. Ynp8@cdc.gov. 6. The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China. Guangda64@hotmail.com. 7. Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan, 430070, Hubei Province, China. Guangda64@hotmail.com.
Abstract
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. METHODS: 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. RESULTS: 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.
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. METHODS: 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. RESULTS: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.
Authors: Daniel Osorio; Yan Zhong; Guanxun Li; Qian Xu; Yongjian Yang; Yanan Tian; Robert S Chapkin; Jianhua Z Huang; James J Cai Journal: Patterns (N Y) Date: 2022-02-01
Authors: Ruth A Houseright; Veronika Miskolci; Oscar Mulvaney; Valeriu Bortnov; Deane F Mosher; Julie Rindy; David A Bennin; Anna Huttenlocher Journal: J Cell Biol Date: 2021-05-28 Impact factor: 10.539