PARP activation and the alteration of vasoactive factors and extracellular matrix protein in retina and kidney in diabetes.
OBJECTIVE
The development of diabetic complications is associated with increased oxidative stress which may damage DNA leading to the activation of nuclear enzyme poly (ADP-ribose) polymerase (PARP). PARP overactivation may further exacerbate the oxidative state of the cell through its consumption of nicotinamide adenine dinucleotide. In diabetic retinopathy and nephropathy, early characteristic features include increased production of vasoactive factors such as endothelin 1 (ET-1) and increased synthesis of extracellular matrix (ECM) proteins such as fibronectin (FN) and its splice variant extra domain B containing (EDB(+)) FN. We investigated the role of PARP in the development of diabetic retinopathy and nephropathy.


METHODS
Two models of diabetic complications were used. PARP-1 knockout mice and their respective wild type controls were fed a 30% galactose diet for 2 months. The rats were given injections of PARP inhibitor 3-aminobenzamide (30 mg/kg/day).


RESULTS
Analysis of the retinal and kidney tissues showed hyperhexosemia-induced oxidative stress and increased expression of ET-1, FN and EDB(+) FN in association with increased transcriptional co-activator p300 along with p300-dependent transcription factors, myocyte enhancing factors 2A and 2C. Furthermore, we showed increased PARP expression in the kidneys and retina of the diabetic rats. PARP blockade in both animal models prevented these hyperhexosemia-induced effects.


CONCLUSIONS
These findings suggests that hyperhexosemia and diabetes causes upregulation of ET-1, FN and EDB(+) FN at the transcriptional level in the retina and kidney via a signaling pathway mediated by PARP and an epigenetic mechanism involving p300 and MEF2 transcription factors. Understanding these mechanisms is important in identifying novel treatment targets.
Xu
Bingying
B
Department of Forensic Science, Kunming Medical College, Kunming, Yunnan, PR China.
Chiu
Jane
J
Feng
Biao
B
Chen
Shali
S
Chakrabarti
Subrata
S
D000818:Animals; D001549:Benzamides; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000209:etiology*; D003930:Diabetic Retinopathy / Q000209:etiology*; D050881:E1A-Associated p300 Protein / Q000502:physiology; D019332:Endothelin-1 / Q000096:biosynthesis*; D004789:Enzyme Activation; D005353:Fibronectins / Q000096:biosynthesis / Q000502:physiology*; D005690:Galactose; D007668:Kidney / Q000503:physiopathology*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D012160:Retina / Q000503:physiopathology*; D015854:Up-Regulation
D001549:Benzamides; D019332:Endothelin-1; D005353:Fibronectins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005690:Galactose