More than just an enzyme: Dipeptidyl peptidase-4 (DPP-4) and its association with diabetic kidney remodelling

Gupta, Shreyasi; Sen, Utpal

doi:10.1016/j.phrs.2019.104391

Cited by 49 publications

(38 citation statements)

References 173 publications

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“…It is well known that both SGLT2 and DPP4 inhibitors generate glucose-dependent and glucose-independent effects in the targeted organs [14][15][16][17][18][19]. In our study, autophagy was reactivated by both empagliflozin and linagliptin, while glucose levels were reduced, but not to the normal range, only under empagliflozin administration.…”

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 43%

“…SGLT2 inhibitors have been shown to enhance sodium excretion and suppress glomerulosclerosis and interstitial fibrosis, inflammation and oxidative stress in diabetic kidney [14][15][16]. In addition, DPP4 inhibitors have been showed to reduce glomerular hypertension and hyperfiltration [17][18][19]. Moreover, empagliflozin has been shown to activate autophagy in tubular cells [20,21].…”

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confidence: 99%

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SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Korbut

Taskaeva

Bgatova

et al. 2020

IJMS

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Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin-linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin-linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes.Int. J. Mol. Sci. 2020, 21, 2987 2 of 22 dedifferentiation. In its turn, the loss or damage of podocytes causes dysfunction of the filtration barrier and increases albuminuria [2]. Some recent studies have indicated an emerging role of autophagy downregulation in diabetic podocytopathy [4][5][6]. Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins [6]. The process is vital for highly differentiated post-mitotic cells, such as neurons and podocytes [7]. A growing body of evidence indicates a critical role of autophagy in maintaining podocyte integrity and renal function [6]. Mice with podocyte-specific deletion of autophagic regulators, such as class III PI3K vacuolar protein sorting 34 (Vps34) and the Atg5 gene, develop early proteinuria, progressive glomerulosclerosis, and renal failure [6]. Accordingly, autophagy is considered a potential therapeutic target for renal protection [8,9].Sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidylpeptidase-4 (DPP4) inhibitors are promising antidiabetic agents introduced into clinical practice in the last decade. The antihyperglycemic effect of SGLT2 inhibitors is mediated by increment of glucosuria, while DPP4 inhibitors realize their activity through an increase in the half-life of incretin hormones. Both SGLT2 and DPP4 inhibitors demonstrated renal protective...

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Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 43%

mentioning

confidence: 99%

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Korbut

Taskaeva

Bgatova

et al. 2020

IJMS

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“…In addition to their blood glucose‐lowering actions, these drugs also show the promise in the treatment of renal diseases 48‐50 . The glucose‐lowering effect of DPP4 inhibitors is mostly mediated by inhibition of islet DPP4 activity to protect the concentration of DPP4 substrates (GLP‐1 and GIP) from degradation and directly stimulates insulin secretion 51 . Recent studies suggest the renal benefits of DPP4 inhibitors in animal models of both diabetic and nondiabetic CKD 14,15 .…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Dong

et al. 2020

FASEB j.

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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.

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“…In the G1 and G2 subgroups, eGFR decreased at 6 months but remained constant thereafter, whereas the median eGFR in patients with renal impairment did not change markedly over the 3-year period. Some DPP4 inhibitors were reported to improve the albumin to creatinine ratio without an improvement in eGFR [54]. Although the degree of change in eGFR varied among patients and between time points in the RUBY surveillance, we believe further studies are needed to evaluate the effects of teneligliptin on the kidneys.…”

Section: Safety In Patients With Renal Impairmentmentioning

confidence: 92%

Long-Term, Real-World Safety and Efficacy of Teneligliptin: A Post-Marketing Surveillance of More Than 10,000 Patients with Type 2 Diabetes in Japan

et al. 2019

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Introduction: Teneligliptin is a dipeptidyl peptidase 4 inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. We performed a long-term postmarketing surveillance (RUBY) to obtain realworld evidence regarding the safety and efficacy of teneligliptin in Japan. Methods: This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs) and laboratory variables. Data were evaluated in all patients and in patients divided according to baseline renal function across categories of estimated glomerular filtration rate (G1-G5) and dialysis. Safety was assessed as the incidence of ADRs and efficacy was assessed in terms of glycaemic control, for up to 3 years. Results: Of 11,677 patients registered, 10,696 and 10,249 were evaluable for safety and efficacy analyses, respectively. The median duration of exposure was 1096 days. ADRs occurred in 412 patients (3.85%) and were serious in 117 patients (1.09%). The most frequent ADR class was gastrointestinal disorders (0.68%), which included constipation. There were no new ADRs warranting attention beyond those already described in teneligliptin's package insert. ADRs and serious ADRs in renal function subgroups occurred in 3.24-7.14% and 0.65-5.36% in G1-G5, and 4.49% and 1.92% in patients on Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11298191.

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More than just an enzyme: Dipeptidyl peptidase-4 (DPP-4) and its association with diabetic kidney remodelling

Cited by 49 publications

References 173 publications

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

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

Long-Term, Real-World Safety and Efficacy of Teneligliptin: A Post-Marketing Surveillance of More Than 10,000 Patients with Type 2 Diabetes in Japan

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