Anti-inflammatory effects of pigment epithelium-derived factor in diabetic nephropathy.
Previously, we have reported that pigment epithelium-derived factor (PEDF) ameliorates albuminuria and inhibits matrix protein deposition in the kidney of streptozotocin (STZ)-induced diabetic rats, suggesting a renoprotective effect of PEDF in early stages of diabetic nephropathy. As inflammation is a major contributor to the development and progression of diabetic nephropathy, we examined in the present study whether PEDF inhibits renal inflammation in diabetic kidney. Diabetic rats received an intravenous injection of an adenovirus expressing PEDF (Ad-PEDF) or the same titer of a control virus. Three wk after the injection, diabetic rats treated with the control virus showed significantly elevated renal levels of proinflammatory factors such as ICAM-1, MCP-1, TNF-alpha, and VEGF compared with age-matched nondiabetic controls. Ad-PEDF effectively suppressed the overexpression of these proinflammatory factors in diabetic kidneys. In cultured primary human renal mesangial cells (HMC), the high-glucose medium-induced upregulation of VEGF and MCP-1 was largely blocked by PEDF. Furthermore, PEDF inhibited high glucose-induced activation of NF-kappaB, a key transcription factor mediating inflammatory responses, and hypoxia-inducible factor-1, a major activator of VEGF expression in HMC. These results suggest that the renoprotective effect of PEDF against diabetic nephropathy may be partially through its anti-inflammatory activity, likely by blocking the NF-kappaB and HIF-1 pathways.
Wang
Joshua J
JJ
Department of Medicine Endocrinology and Cell Biology, Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Zhang
Sarah X
SX
Mott
Robert
R
Chen
Ying
Y
Knapp
Ryan R
RR
Cao
Wei
W
Ma
Jian-xing
JX
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003470:Culture Media; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011914:Rats, Inbred BN; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D014178:Translocation, Genetic; D000099174:Pigment Epithelium-Derived Factor
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003470:Culture Media; D016207:Cytokines; D005136:Eye Proteins; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D009414:Nerve Growth Factors; D015843:Serpins; D051996:Transcription Factor RelA; D000099174:Pigment Epithelium-Derived Factor