title: Repeated systemic administration of human adipose-derived stem cells attenuates overt diabetic nephropathy in rats.
abstract: Adipose-derived stem cells (ASCs) can alleviate acute kidney injury and promote kidney cell regeneration and repair. To investigate the role of ASCs in diabetic nephropathy (DN), Sprague-Dawley rats were made diabetic by intraperitoneal injection of streptozotocin (STZ) after uninephrectomy. After 12 weeks, proteinuria was well established. Five times of 5×10(6) human ASCs repeatedly injected through a tail vein at 4 weekly intervals. A reduction in proteinuria was not observed in diabetic rats until 24 weeks. However, urinary protein excretion was significantly suppressed at 28 weeks and persisted up to 32 weeks after STZ treatment. ASC treatment significantly attenuated glomerulus hypertrophy and tubular interstitial injury, and led to the downregulation of WT-1 and synaptopodin expression. CFSE labeled ASCs were injected into DN rats via the tail vein. Within 24 h after injection, the cells were detected in lung, spleen, and peritubular regions, but rarely in pancreas. Human Alu gene expression was detected in lung and spleen up to 4 weeks after ASCs injection. ASC treatment did not improve hyperglycemia or pancreatic damage. In vitro, recombinant human glial cell line-derived neurotrophic factor (GDNF) prevented podocyte injury by high glucose similarly to ASC-conditioned medium. After blocking GDNF in ASC-CM with neutralizing antibody, the therapeutic effect of ASC-CM was significantly decreased. ASCs cocultured with podocytes restored the downregulation of synaptopodin expression, which was weakened by GDNF-RNA interfering. These findings indicate that repeated intravenous ASC can reduce diabetic kidney damage in rats even at the progressive stage, and promote podocyte recovery via GDNF secretion.
authors.affiliation: 1 State Key Laboratory of Kidney Disease, Department of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College , Beijing, China .
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Kanghua
authors.initials: K
authors.lastname: Li
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Liu
authors.forename: Diangeng
authors.initials: D
authors.lastname: Li
authors.forename: Congjuan
authors.initials: C
authors.lastname: Luo
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Cui
authors.forename: Fei
authors.initials: F
authors.lastname: Zhu
authors.forename: Robert Chunhua
authors.initials: RC
authors.lastname: Zhao
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology / Q000628:therapy*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology / Q000628:therapy; D006984:Hypertrophy; D007515:Islets of Langerhans / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000150:complications / Q000473:pathology / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor