Diabetes‐induced overexpression of endothelin‐1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP‐ribose) polymerase activation

• Published in: The FASEB journal 2003-08, Vol.17 (11), p.1-18
• Main Authors: Minchenko, Alexander G., Stevens, Martin J., White, Lauren, Abatan, Omorodola I., Komjáti, Katalin, Pachter, Pal, Szabó, Csaba, Obrosova, Irina G.
• Format: Article
• Language: English
• Subjects: 1,5-isoquinolinediol; 3-aminobenzamide; Animals; Benzamides - pharmacology; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; diabetic nephropathy; Endothelin-1 - biosynthesis; Endothelin-1 - genetics; Enzyme Activation; Enzyme Inhibitors - pharmacology; Gene Expression Regulation; Isoquinolines; Kidney Cortex - metabolism; Kidney Glomerulus - enzymology; Kidney Glomerulus - pathology; Kidney Tubules - enzymology; Kidney Tubules - pathology; Models, Biological; Oxidative Stress; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - metabolism; poly(ADP-ribosyl)ation; Quinolines - pharmacology; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin - biosynthesis; Receptors, Endothelin - genetics; RNA, Messenger - biosynthesis; streptozotocin-diabetic rat
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.03-0013fje

ABSTRACT We hypothesize that poly (ADP‐ribosyl)ation, that is, poly (ADP‐ribose) polymerase (PARP)‐dependent transfer of ADP‐ribose moieties from NAD to nuclear proteins, plays a role in diabetic nephropathy. We evaluated whether PARP activation is present and whether two unrelated PARP inhibitors, 3‐aminobenzamide (ABA) and 1,5‐isoquinolinediol (ISO), counteract overexpression of endothelin‐1 (ET‐1) and ET receptors in the renal cortex in short‐term diabetes. The studies were performed in control rats and streptozotocin‐diabetic rats treated with/without ABA or ISO (30 and 3 mg*kg−1*day−1, intraperitoneally, for 2 weeks after 2 weeks of diabetes). Poly (ADP‐ribose) immunoreactivity was increased in tubuli, but not glomeruli, of diabetic rats and this increase was corrected by ISO, whereas ABA had a weaker effect. ET‐1 concentration (ELISA) was increased in diabetic rats, and this elevation was blunted by ISO. ET‐1, ET(A), and ET(B) mRNA (ribonuclease protection assay), but not ET‐3 mRNA (RT/PCR), abundance was increased in diabetic rats, and three variables were, at least, partially corrected by ISO. ABA produced a trend towards normalization of ET‐1 concentration and ET‐1, ET(A), and ET(B) mRNA abundance, but the differences with untreated diabetic group were not significant. Poly(ADP‐ribosyl)ation is involved in diabetes‐induced renal overexpression of ET‐1 and ET receptors. PARP inhibitors could provide a novel therapeutic approach for diabetic complications including nephropathy, and other diseases that involve the endothelin system.