Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.
The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.
Lal
M A
MA
Department of Women and Child Health, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Körner
A
A
Matsuo
Y
Y
Zelenin
S
S
Cheng
S X
SX
Jaremko
G
G
DiBona
G F
GF
Eklöf
A C
AC
Aperia
A
A
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001552:Benzazepines / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010422:Pentanones / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
D000975:Antioxidants; D001552:Benzazepines; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010422:Pentanones; C057364:nitecapone; D012964:Sodium; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase