Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases

Abstract

Background Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear. Methods The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte. Results DPP-4 activity under normal conditions was observed in some Bowman’s capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes. Conclusions DPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

“…Subsequently, Dpp4 expression was found to be significantly up-regulated in DKD podocytes, with no significant difference in other cell clusters ( Figure 1B ). This is consistent with previous studies reporting increased DPP4 activity in podocytes at DKD status ( Kubo et al, 2020 ). Further, in the DKD model, DPP4 inhibitors were shown to improve podocyte function ( Jung et al, 2015 ; Eun Lee et al, 2016 ; Kubo et al, 2020 ).…”

“…This is consistent with previous studies reporting increased DPP4 activity in podocytes at DKD status ( Kubo et al, 2020 ). Further, in the DKD model, DPP4 inhibitors were shown to improve podocyte function ( Jung et al, 2015 ; Eun Lee et al, 2016 ; Kubo et al, 2020 ).…”

Renoprotective Effects of DPP-4 Inhibitors

“…Accordingly, they found that adriamycin increased the DPP-4 activity in cultured podocytes, with this effect inhibited by saxaglptin. Furthermore, saxagliptin prevented podocyte damage by maintaining synaptopodin and RhoA, which are important components of the cytoskeleton structure of podocytes [ 97 ]. Sitagliptin has been shown to prevent apoptotic cell death in the kidney of ZDF-rats, as indicated by reductions in the BAX/Bcl-2 ratio, Bid protein levels, and numbers of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the kidney sections [ 98 ].…”

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 ].…”