Dipeptidyl peptidase IV (DPPIV) is an
exopeptidase that modulates the function of several substrates, among which
insulin-releasing
incretin hormones are the most well known. DPPIV also modulate substrates involved in
inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of
LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal
fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral
ureteral obstruction (UUO) and were treated with
LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced
after treatment with
LC15-0444. Administration of
LC15-0444 resulted in a significant decrease in
albuminuria, urinary excretion of
8-isoprostane, and renal
fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and
LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFβ1,
toll-like receptor 4, high-mobility group box-1,
NADPH oxidase 4, and NF-κB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted
therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by
glucagon-like peptide-1.