Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in
diabetic nephropathy. We have recently found that
linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental
diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4-deficient F344/DuCrl/Crlj rats diabetic by injection of
streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in
streptozotocin-induced diabetic rats. Compared with control rats at 9 and 11 weeks old,
body weight and heart rates were significantly lower, while fasting
blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of
body weight, fasting
blood glucose and
lipid parameters between the two diabetic rat strains. AGEs,
8-hydroxy-2'-deoxyguanosine (8-OHdG) and
nitrotyrosine levels in the kidney, renal gene expression of RAGE and
intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and
albumin, and the ratio of renal to
body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1
diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing
diabetic nephropathy.