Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy.
BACKGROUND
Serotonin (5-HT) is involved in vascular inflammation and atherosclerogenesis. Serum 5-HT concentrations are elevated in diabetes, and 5-HT is involved in diabetic vasculopathies. Sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, has renoprotective effects, but its effect in diabetic nephropathy is not elucidated. The aim of this study was to examine the effects of sarpogrelate on endothelial dysfunction in rats with streptozotocin (STZ)-induced diabetes.


METHODS
Rats with STZ-induced diabetes were either untreated or treated with sarpogrelate (30 mg/kg P.O.) for 8 weeks. At the end of the experiment, we measured urinary albumin excretion, serum adiponectin concentration and platelet-derived microparticles. Intraglomerular coagulation was detected by immunostaining for platelets. Production of renal reactive oxygen species (ROS) and nitric oxide (NO) was investigated by confocal laser microscopy and used as an index of glomerular endothelial dysfunction.


RESULTS
Diabetic nephropathy was associated with enhanced production of ROS and diminished bioavailable NO in the glomeruli. Treatment with sarpogrelate improved ROS/NO imbalance in glomeruli, suppressed platelet aggregation in glomeruli, reduced platelet-derived microparticles, increased serum adiponectin level and reduced the level of albuminuria, compared with non-treated diabetic rats.


CONCLUSIONS
Our results indicate that sarpogrelate improves endothelial function in rats with STZ-induced diabetes through a reduction of glomerular platelet activation and an increase in serum adiponectin concentrations and suggest that sarpogrelate is potentially useful for the treatment of diabetic nephropathy.
Kobayashi
Shinya
S
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Satoh
Minoru
M
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan. msatoh@med.kawasaki-m.ac.jp.
Namikoshi
Tamehachi
T
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Haruna
Yoshisuke
Y
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Fujimoto
Sohachi
S
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Arakawa
Sayaka
S
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Komai
Norio
N
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Tomita
Naruya
N
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Sasaki
Tamaki
T
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
Kashihara
Naoki
N
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan.
D000080242:8-Hydroxy-2'-Deoxyguanosine; D052242:Adiponectin / Q000097:blood; D000419:Albuminuria / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000652:urine; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013386:Succinates / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D052242:Adiponectin; C499920:Adipoq protein, rat; D017382:Reactive Oxygen Species; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D009569:Nitric Oxide; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019001:Nitric Oxide Synthase; D003849:Deoxyguanosine