Regulating Autophagy as a Therapeutic Target for Diabetic Nephropathy

Kitada, Munehiro; Ogura, Yoshio; Monno, Itaru; Koya, Daisuke

doi:10.1007/s11892-017-0879-y

Cited by 83 publications

(73 citation statements)

References 82 publications

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“…Kidney macroautophagy is regulated by mammalian target of rapamycin (mTOR) [8,38,39], AMP-activated protein kinase (AMPK) [8], SIRT1 [8], Wnt/β-catenin [40], and TGF-β [41] signaling pathways. The downregulation of glomerular autophagy under hyperglycemic condition is considered a result of activation of mTOR pathway [8,42] or suppression of AMPK activity and SIRT1 signaling [37,43,44]. In our study, glomerular autophagy was related negatively to parameters of glycemic status, fructosamine and glycated albumin.…”

Section: Suppression Of Renal Autophagy In Diabetes: Markers and Mechsupporting

confidence: 46%

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: Suppression Of Renal Autophagy In Diabetes: Markers and Mechsupporting

confidence: 46%

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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“…Diabetic nephropathy (DN) remains the leading cause of endstage renal disease worldwide. Although glomerulopathy is considered the main feature of DN, it is the extent of tubulointerstitial injury that ultimately determines the rate of depletion of renal function [1] . A growing body of evidence indicates that the tubulointerstitium plays a critical role in the pathogenesis of DN [2] .…”

Section: Introductionmentioning

confidence: 99%

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

Zhang

et al. 2018

Acta Pharmacol Sin

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Inflammation and lipid disorders play crucial roles in synergistically accelerating the progression of diabetic nephropathy (DN). In this study we investigated how inflammation and lipid disorders caused tubulointerstitial injury in DN in vivo and in vitro. Diabetic db/db mice were injected with 10% casein (0.5 mL, sc) every other day for 8 weeks to cause chronic inflammation. Compared with db/db mice, casein-injected db/db mice showed exacerbated tubulointerstitial injury, evidenced by increased secretion of extracellular matrix (ECM) and cholesterol accumulation in tubulointerstitium, which was accompanied by activation of the CXC chemokine ligand 16 (CXCL16) pathway. In the in vitro study, we treated HK-2 cells with IL-1β (5 ng/mL) and high glucose (30 mmol/L). IL-1β treatment increased cholesterol accumulation in HK-2 cells, leading to greatly increased ROS production, ECM protein expression levels, which was accompanied by the upregulated expression levels of proteins in the CXCL16 pathway. In contrast, after CXCL16 in HK-2 cells was knocked down by siRNA, the IL-1β-deteriorated changes were attenuated. In conclusion, inflammation accelerates renal tubulointerstitial lesions in mouse DN via increasing the activity of CXCL16 pathway.

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“…It is possible that RAPAmediated attenuation of mTORC1 activation in podocytes reduces the development of diabetic nephropathy and subsequent renal damage 9,10 through activation of podocyte autophagy. [53][54][55][56] Similar dietary RAPA-mediated reductions in ACR and improvement in kidney histology were described using NONcNZO10/LtJ (NcZ10) mice, a polygenic model of obesity and T2D. 36 RAPA inhibition of the mTOR pathway has been shown to be protective against the development of hypertrophic and uremic cardiomyopathy, 29 cardiomyopathy caused by inactivation of PTEN, 30 and in partially nephrectomized rats treated with marinobufagenin, a profibrotic cardiotonic steroid that is elevated in patients with renal failure.…”

Section: Discussionmentioning

confidence: 77%

“…It is possible that RAPA-mediated attenuation of mTORC1 activation in podocytes reduces the development of diabetic nephropathy and subsequent renal damage 9,10 through activation of podocyte autophagy. 53–56 Similar dietary RAPA-mediated reductions in ACR and improvement in kidney histology were described using NONcNZO10/LtJ (NcZ10) mice, a polygenic model of obesity and T2D. 36 …”

Section: Discussionmentioning

confidence: 90%

Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J‐Lepr^db mice

Reifsnyder

Ryzhov

Anunciado‐Koza

et al. 2018

Annals of the New York Academy of Sciences

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Rapamycin (RAPA), an inhibitor of mTORC signaling, has been shown to extend life span in mice and other organisms. Recently, animal and human studies have suggested that inhibition of mTORC signaling can alleviate or prevent the development of cardiomyopathy. In view of this, we used a murine model of type 2 diabetes (T2D), BKS-Lepr , to determine whether RAPA treatment can mitigate the development of T2D-induced cardiomyopathy in adult mice. Female BKS-Lepr mice fed diet supplemented with RAPA from 11 to 27 weeks of age showed reduced weight gain and significant reductions of fat and lean mass compared with untreated mice. No differences in plasma glucose or insulin levels were observed between groups; however, RAPA-treated mice were more insulin sensitive (P < 0.01) than untreated mice. Urine albumin/creatinine ratio was lower in RAPA-treated mice, suggesting reduced diabetic nephropathy and improved kidney function. Echocardiography showed significantly reduced left ventricular wall thickness in mice treated with RAPA compared with untreated mice (P = 0.02) that was consistent with reduced heart weight/tibia length ratios, reduced myocyte size and cardiac fibrosis measured by histomorphology, and reduced mRNA expression of Col1a1, a marker for cardiomyopathy. Our results suggest that inhibition of mTORC signaling is a plausible strategy for ameliorating complications of obesity and T2D, including cardiomyopathy.

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Regulating Autophagy as a Therapeutic Target for Diabetic Nephropathy

Cited by 83 publications

References 82 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

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J‐Lepr^db mice

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Regulating Autophagy as a Therapeutic Target for Diabetic Nephropathy

Cited by 83 publications

References 82 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

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J‐Leprdb mice

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Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J‐Lepr^db mice