Poly(Adenosine 5'-Diphosphate-Ribose) Polymerase Inhibition Counteracts Multiple Manifestations of Experimental Type 1 Diabetic Nephropathy Export

@article{citeulike:6055000, abstract = {This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg-1 {middle dot} d-1 ip and 30 mg/kg-1 {middle dot} d-1, respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-{beta}1, vascular endothelial growth factor, endothelin-1, TNF-{alpha}, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-{alpha} excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-{alpha}1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies. 10.1210/en.2009-0628}, author = {Drel, Viktor R. and Xu, Weizheng and Zhang, Jie and Pavlov, Ivan A. and Shevalye, Hanna and Slusher, Barbara and Obrosova, Irina G.}, citeulike-article-id = {6055000}, citeulike-linkout-0 = {http://dx.doi.org/10.1210/en.2009-0628}, citeulike-linkout-1 = {http://endo.endojournals.org/content/150/12/5273.abstract}, citeulike-linkout-2 = {http://endo.endojournals.org/content/150/12/5273.full.pdf}, citeulike-linkout-3 = {http://endo.endojournals.org/cgi/content/abstract/150/12/5273}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/19854869}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=19854869}, day = {1}, doi = {10.1210/en.2009-0628}, issn = {1945-7170}, journal = {Endocrinology}, keywords = {dn, parp, rat, ros, stz, tgfb}, month = {December}, number = {12}, pages = {5273--5283}, posted-at = {2009-11-02 02:21:21}, priority = {2}, title = {Poly(Adenosine 5'-Diphosphate-Ribose) Polymerase Inhibition Counteracts Multiple Manifestations of Experimental Type 1 Diabetic Nephropathy}, url = {http://dx.doi.org/10.1210/en.2009-0628}, volume = {150}, year = {2009} }

TY - JOUR ID - citeulike:6055000 L3 - citeulike-article-id:6055000 N2 - This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg-1 {middle dot} d-1 ip and 30 mg/kg-1 {middle dot} d-1, respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-{beta}1, vascular endothelial growth factor, endothelin-1, TNF-{alpha}, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-{alpha} excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-{alpha}1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies. 10.1210/en.2009-0628 IS - 12 JF - Endocrinology SN - 1945-7170 EP - 5283 TI - Poly(Adenosine 5'-Diphosphate-Ribose) Polymerase Inhibition Counteracts Multiple Manifestations of Experimental Type 1 Diabetic Nephropathy VL - 150 SP - 5273 KW - dn KW - parp KW - rat KW - ros KW - stz KW - tgfb AU - Drel, Viktor AU - Xu, Weizheng AU - Zhang, Jie AU - Pavlov, Ivan AU - Shevalye, Hanna AU - Slusher, Barbara AU - Obrosova, Irina PY - 2009/12/01/ UR - http://dx.doi.org/10.1210/en.2009-0628 ER -