Activation of EphA1-Epha receptor axis attenuates diabetic nephropathy in mice.
The Eph family of receptor tyrosine kinases serves as key modulators of various cellular functions, including inflammation, hypertrophy and fibrosis. Recent analyses have revealed that a member of the Eph family, EphA1, plays a pivotal role in regulating insulin metabolism and kidney injury. However, the importance of EphA1 in diabetic nephropathy has not been recognized. We established a diabetic nephropathy mouse model using a high-fat diet and streptozotocin (STZ) injection. Then, the recombinant adeno-associated virus type 9 (AAV9) overexpressing EphA1 or a negative control was injected locally into the kidney. Metabolite testing and histopathological analyses of kidney fibrosis, pancreatic islet function and signaling pathways were evaluated. Our study showed that hyperglycemia, insulin resistance, and renal fibrosis accompanied the deterioration of kidney function in diabetic mice. The overexpression of EphA1 in the kidney attenuated renal fibrosis and improved kidney function but did not affect systemic glucose metabolism and pancreatic islet function. Furthermore, the overexpression of EphA1 decreased the phosphorylation of ERK1/2, JNK and MYPT1 (a substrate of Rho kinase). The overexpression of EphA1 can be therapeutically targeted to inhibit diabetic renal fibrosis, which suggests that the EphA1-Epha receptor axis may be a novel therapy target for diabetic nephropathy. Mechanistically, the overexpression of EphA1 could inhibit MAPK and the Rho pathway in diabetic kidneys.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Yihui
Y
Li
Department of Anesthesiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Hongdan
H
Yan
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Feng
F
Wang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Shanying
S
Huang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Yun
Y
Zhang
Department of Geriatric Medicine, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Zhihao
Z
Wang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Ming
M
Zhong
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China. Electronic address: zhangweisdu7@163.com.
Wei
W
Zhang
D000818:Animals; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D059305:Diet, High-Fat; D036382:Ephrin-A1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism; D036082:Receptor, EphA1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin
D036382:Ephrin-A1; D013311:Streptozocin; D036082:Receptor, EphA1; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; D043263:Myosin-Light-Chain Phosphatase; C510645:Ppp1r12a protein, mouse
Adeno-associated virus; Diabetes; EphA1; Fibrosis; Nephropathy