Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3‐dependent mitochondrial homeostasis through SDF‐1α/CXCR4 pathway

Abstract

Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase‐4 (DPP4) inhibitors are widely used antihyperglycemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). However, their underlying mechanism remains unclear. In this study, DPP4 upregulation, mitochondrial fragmentation, and altered mitochondrial dynamics‐associated protein expression were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin‐stimulated tubular cells. The inhibition of DPP4 by sitagliptin (Sita) ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion‐fission disorder and tubular cell injury in albumin‐treated HK‐2 cells. Downstream of DPP4, the SDF‐1α/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita treatment, this signaling pathway was restored, and the mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in the mitochondria of tubular cells, and this effect was weakened by overloading albumin and by CXCR4 siRNA treatment, suggesting a possible link between DPP4‐mediated SDF‐1α/CXCR4/STAT3 signaling and mitochondrial dysfunction in diabetic tubular cells. The results suggest that a novel mechanism links the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF‐1α/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD.

Tanshinone IIA Ameliorates Streptozotocin-Induced Diabetic Nephropathy, Partly by Attenuating PERK Pathway-Induced Fibrosis

“…IHC staining was scored independently by two pathologists [percentage of positive cells: five categories: 0 (<10%), 1 (10-25%), 2 (25-50%), 3 (50-75%), and 4 (75-100%); intensity: four categories (from low to high): 0, 1, 2, and 3; and a final IHC staining score (intensity score × percentage score)] was determined. 18…”

“…The membranes were blocked with 5% non-fat dry milk at 37°C for 1 h, and the proteins were probed against respective primary antibodies accordingly to previously published methods. 18 The β-actin was used as the internal control.…”

Excessively Enlarged Mitochondria in the Kidneys of Diabetic Nephropathy

“…Zhang et al showed that a renal tubular injury in diabetic mice was suppressed by sitagliptin treatment. Moreover, sitagliptin restored mitochondrial fragmentation by regulating Drp1 expression and phosphorylation in the kidneys of diabetic mice and albumin-overloaded human kidney-2 (HK-2) cells [ 96 , 97 ]. In addition, the β 2 -adrenergic receptor (AR) agonist formoterol induced mitochondrial biogenesis and promoted recovery from AKI [ 98 ].…”

Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases

“…Under diabetic conditions, excessive DPP4 would facilitate the transformation of its substrate SDF-1α into cleaved form, thus suppressing the SDF-1α/CXCR4/STAT3 pathway and impeding the translocation of STAT3 S727 into mitochondria. Diminished interaction of STAT3 and the mitochondrial fusion-associated protein OPA1 contributed to mitochondrial dysfunction in diabetic tubular cells, inducing DN progression [ 95 ].…”