Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats.
Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury.
Nephrology Research Laboratories, Nephrology R&D unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Mariko
M
Sakai
Nephrology Research Laboratories, Nephrology R&D unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Masako
M
Uchii
Translational Research Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Kensuke
K
Myojo
Nephrology Research Laboratories, Nephrology R&D unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Tetsuya
T
Kitayama
Nephrology Research Laboratories, Nephrology R&D unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. Electronic address: shunji.kunori@kyowa-kirin.co.jp.
Shunji
S
Kunori
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D019610:Cytoprotection; D004151:Dipeptides / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020303:Rats, Inbred Dahl; D000068900:Sitagliptin Phosphate / Q000494:pharmacology
D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; D000218:Adamantane; D000068900:Sitagliptin Phosphate
Dahl salt-sensitive hypertensive rat; Kidney injury; Renal dipeptidyl peptidase-4; Saxagliptin