Stromal cell–derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy

Abstract

The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice. The DPP-4 inhibitor linagliptin, but not the GLP-1R agonist liraglutide, further augmented renal SDF-1 expression in both Glp1r(+/+) and Glp1r(-/-) diabetic-prone mice. Along with upregulation of renal SDF-1 expression, the progression of albuminuria, glomerulosclerosis, periglomerular fibrosis, podocyte loss, and renal oxidative stress was suppressed in linagliptin-treated Glp1r(+/+) diabetic-prone mice. Linagliptin treatment increased urinary sodium excretion and attenuated the increase in glomerular filtration rate which reflects glomerular hypertension and hyperfiltration. In contrast, selective SDF-1 receptor blockade with AMD3100 reduced urinary sodium excretion and aggravated glomerular hypertension in the Glp1r(+/+) diabetic-prone mice. Thus, DPP-4 inhibition, independent of GLP-1R signaling, contributes to protection of the diabetic kidney through SDF-1-dependent antioxidative and antifibrotic effects and amelioration of adverse renal hemodynamics.

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

“…These results showed that DPP-4 inhibition could have reno-protective effects through glucagonlike peptide-1 receptor (GLP-1R) and also through other substrates such as stromal derived factor-1 alpha (SDF-1a) independent of GLP-1R (Takashima et al 2016).…”

“…These findings were counteracted with linagliptin treatment (Nistala et al 2014). Moreover, (Takashima et al 2016) used Glp1r -/-diabetic-prone Akita mice to show that linagliptin enhanced renal SDF-1 expression leading to improved renal outcomes, independent of GLP-1R signalling, which were counteracted using AMD3100, a selective SDF-1 receptor blocker. Thus the available data on SDF-1 in the setting of diabetic nephropathy remain controversial and need more investigation.…”

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…The administration of a GLP‐1 receptor agonist or a DPP‐4 inhibitor acts to attenuate the activity of NHE3 . However, the ability of DPP‐4 inhibitors to modulate NHE3 is not related to their action to prevent the degradation of GLP‐1; instead, DPP‐4 inhibitors appear to potentiate another endogenous natriuretic peptide that is degraded by DPP‐4 (potentially, stromal cell‐derived factor‐1) . This finding explains why the molecular pathways by which GLP‐1 receptor agonists and DPP‐4 inhibitors act to attenuate NHE3 activity are distinct; GLP‐1 receptor agonism exerts its effects on NHE3 through protein kinase A, whereas DPP‐4 inhibition acts through a tyrosine kinase pathway .…”

The Difference between SGLT2 and DPP-4 Inhibitors on Glucose Fluctuation in Patients with Type 2 Diabetes

“…Previous in vitro and in vivo studies have verified that incretin agents, including DPP-4 inhibitors, exert renal protective effects against increased renal oxidative stress under hyperglycemic conditions via cAMP-PKA activation [37]; stromal cell-derived factor 1 upregulation and stromal cellderived factor 1-dependent anti-oxidative and anti-fibrotic effects on the diabetic kidney [38]; and inhibition of endothelialto-mesenchymal transition and renal fibrosis via suppression of endothelium DPP-4 and integrin β1 levels [39]. In clinical use, some pooled analysis and randomized controlled trials using DPP-4 inhibitors resulted in significant improvement of albuminuria [40,41].…”