Vildagliptin restores renal myogenic function and attenuates renal sclerosis independently of effects on blood glucose or proteinuria in zucker diabetic fatty rat.
Type 2 diabetes mellitus (T2DM) is associated with risk for chronic kidney disease (CKD), which is associated with a decrease in renal myogenic tone - part of renal autoregulatory mechanisms. Novel class of drugs used for the treatment of T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors, have protective effects on the cardiovascular system. A Zucker Diabetic Fatty (ZDF) rat is an animal model of T2DM that displays progressive nephropathy in which inflammation leads to initiation of renal fibrosis and CKD. We hypothesized that CKD in the ZDF rat is related to decrease in myogenic constriction (MC) of intrarenal arteries and that treatment with the DPP-4 inhibitor, vildagliptin, prevents such changes. Renal arteries isolated from 25 weeks old lean, ZDF and ZDF treated with vildagliptin (n=7 in each group) were transferred to an arteriograph to assess agonist and pressure induced contractile responses. Furthermore, blood glucose, proteinuria, focal glomerulosclerosis (FGS) and p22phox mRNA expression of renal tissue were measured. Compared to lean controls, ZDF had significantly increased plasma glucose and cholesterol levels, focal glomerulosclerosis and interstitial α-SMA expression, and urinary protein excretion. ZDF rats also had impaired MC of renal arteries and increased renal p22phox expression. Vildagliptin did not affect plasma glucose levels or proteinuria, but effectively decreased glomerulosclerosis and restored MC and p22phox expression to the levels found in lean rats. Based on these data, it can be suggested that vildagliptin treatment protects diabetic rats from the loss of renal vascular reactivity and the development of glomerulosclerosis perhaps secondary to a reduction in oxidative stress.
Peter
P
Vavrinec
Robert H
RH
Henning
Sjoerd W
SW
Landheer
Yumei
Y
Wang
Leo E
LE
Deelman
Richard P E van
RP
Dokkum
Department of Pharmacology and Toxicology Comenius University in Bratislava, Faculty of Pharmacy, Odbojarov 10, 83232, Bratislava, Slovak Republic. vavrinec@fpharm.uniba.sk.
Hendrik
H
Buikema
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D012598:Sclerosis / Q000188:drug therapy / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D000077597:Vildagliptin
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane