Glucose-independent renoprotective mechanisms of the tissue dipeptidyl peptidase-4 inhibitor, saxagliptin, in Dahl salt-sensitive hypertensive rats

• Published in: European journal of pharmacology 2016-07, Vol.783, p.56-63
• Main Authors: Uchii, Masako, Kimoto, Naoya, Sakai, Mariko, Kitayama, Tetsuya, Kunori, Shunji
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Adamantane - therapeutic use; Animals; Blood Glucose - metabolism; Blood Pressure - drug effects; Creatinine - blood; Cytoprotection - drug effects; Dipeptides - pharmacology; Dipeptides - therapeutic use; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Fibrosis; Gene Expression Regulation - drug effects; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - pathology; Hypertension - physiopathology; Inflammation; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidney injury; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - pathology; Male; Myocardium - pathology; Organ Size - drug effects; Rats; Rats, Inbred Dahl; Renal dipeptidyl peptidase-4; Saxagliptin; Sodium - urine
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.04.005

Although previous studies have shown an important role of renal dipeptidyl peptidase-4 (DPP-4) inhibition in ameliorating kidney injury in hypertensive rats, the renal distribution of DPP-4 and mechanisms of renoprotective action of DPP-4 inhibition remain unclear. In this study, we examined the effects of the DPP-4 inhibitor saxagliptin on DPP-4 activity in renal cells (using in situ DPP-4 staining) and on renal gene expression related to inflammation and fibrosis in the renal injury in hypertensive Dahl salt-sensitive (Dahl-S) rats. Male rats fed a high-salt (8% NaCl) diet received vehicle (water) or saxagliptin (12.7mg/kg/day) for 4 weeks. Blood pressure (BP), serum glucose and 24-h urinary albumin and sodium excretions were measured, and renal histopathology was performed. High salt-diet increased BP and urinary albumin excretion, consequently resulting in glomerular sclerosis and tubulointerstitial fibrosis. Although saxagliptin did not affect BP and blood glucose levels, it significantly ameliorated urinary albumin excretion. In situ staining showed DPP-4 activity in glomerular and tubular cells. Saxagliptin significantly suppressed DPP-4 activity in renal tissue extracts and in glomerular and tubular cells. Saxagliptin also significantly attenuated the increase in inflammation and fibrosis-related gene expressions in the kidney. Our results demonstrate that saxagliptin inhibited the development of renal injury independent of its glucose-lowering effect. Glomerular and tubular DPP-4 inhibition by saxagliptin was associated with improvements in albuminuria and the suppression of inflammation and fibrosis-related genes. Thus, local glomerular and tubular DPP-4 inhibition by saxagliptin may play an important role in its renoprotective effects in Dahl-S rats.