DPP4 beyond glucose homeostasis

Lorenzo GLORIE: DPP4 beyond glucose homeostasis: attenuation of acute kidney injury and diabetic bone loss through DPP4 inhibition

Promotors: Patrick D’Haese, Anja Verhulst

Defense 12/12/2015

DPP4 is an exopeptidase with an important role in protein regulation. It is ubiquitously expressed and can be focoverund on the cellular membrane but also roaming free in the circulation. The substrates of DPP4, a growing list of peptides, have important roles in glucose metabolism (incretins) as well as in neurological and immunological mechanisms. DPP4 inhibitors were developed as a treatment to improve glucose tolerance in type 2 diabetic patients, as they increase the half-life of incretins.

Inhibition of DPP4 exhibits protective effects on ischemic cardiomyopathy and lung injury, associated with anti-inflammatory, anti-oxidative and anti-apoptotic activities. As DPP4 and its substrates are also expressed in the kidney, the potentially therapeutic effect of DPP4 inhibition with vildagliptin in ischemic acute kidney injury was studied in rats undergoing unilateral renal ischemia. DPP4 inhibition resulted in a significant decrease of serum creatinine compared to saline treated animals. Tubular morphology revealed significantly reduced tubular necrosis after vildagliptin treatment indicating a functional protection against ischemia reperfusion injury. DPP4 inhibition also decreased apoptosis and resulted in anti-inflammatory and anti-oxidative effects. DPP4 as well as many DPP4 substrate receptors are also expressed on the surface of active bone cells, and some DPP4 substrates are directly released from active bone cells and surrounding nerve fibers. Some DPP4 substrates are known to positively affect bone metabolism. Menopause and diabetic hyperglycemia are both associated an increased fracture rate combined with increased DPP4 activity. In a model of trabecular boneovariectomy, the effect of DPP4 inhibition with sitagliptin was assessed on the pathophysiological development of osteoporosis. Only a minor effect was observed in the early phase after ovariectomy. The effect was also studied in a rat model of streptozotocin-induced diabetes. Trabecular bone loss, decrease in trabecular number, and increase in trabecular spacing were found to be attenuated through sitagliptin treatment in diabetic rats.

Sitagliptin also prevented cortical bone growth stagnation in diabetic rats, resulting in stronger femora. Effects were independent of glycemic management and associated with a decrease of resorption markers. These results open perspectives for the application of DPP4 inhibitors in future scientific research, and show their potential for further therapeutic development.