Emerging role of podocyte autophagy in the progression of diabetic nephropathy

Yasuda‐Yamahara, Mako; Kume, Shinji; Tagawa, Atsuko; Maegawa, Hiroshi; Uzu, Takashi

doi:10.1080/15548627.2015.1115173

Cited by 83 publications

(76 citation statements)

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“…We have also revealed the reduced expression of LAMP-1 in the renal cortex by western blotting. The results are in agreement with the data from other researches recorded downregulation of autophagy in diabetic kidneys [4,[23][24][25][26].…”

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

confidence: 93%

“…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].…”

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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: Suppression Of Renal Autophagy In Diabetes: Markers and Mechsupporting

confidence: 93%

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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“…Autophagy was reported to be renoprotective in several animal models such as aging and acute kidney injury models [20]. Recently, autophagy was revealed to be particularly important for the maintenance of podocytes, which have only a limited capacity for regeneration [21]. For example, aging mice, with podocyte-specific deletion of autophagy-related genes, exhibited proteinuria and glomerulopathy [9].…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Induces Autophagy and Reduces the Apoptosis of Podocytes Under a Stimulated Condition of Immunoglobulin A Nephropathy

Liang¹,

Jin²,

Lin³

et al. 2017

Kidney Blood Press Res

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Backgroud/Aims: The aim of this study was to investigate the potential renoprotective effect of rapamycin on the autophagy of podocytes treated with the supernatant of mesangial cells cultured with aggregated IgA1 (aIgA1) from immunoglobulin A nephropathy (IgAN) patients. Methods: Monomeric IgA1 (mIgA1) was isolated from the serum of IgAN patients or healthy volunteers, and then transformed to aIgA1 by heating. Subsequently, the aIgA1-mesangial cell supernatant was prepared by collecting the medium of mouse mesangial cells (MSC1097) cultured with aIgA1 (100 mg/L) from different IgAN patients or healthy volunteers for 48 h. Subsequently mouse podocytes (MPC5) were exposed to the supernatant of the aIgA1-mesangial cells for 24 h, using 100 mg/L aIgA1 from healthy volunteers as the control group or 100 mg/L aIgA1 from IgAN patients as the IgANs group, in RPMI 1640 medium. The MPC5 cells in the IgANs+Rap group were cultured with rapamycin (10 nmol/L) and the supernatant of MSC-1097 cells cultured with aIgA1 from IgAN patients in RPMI 1640 medium. Autophagy was assessed by western blot analysis (LC3, p62), electron microscopy, and immunofluorescence staining (LC3, p62, and CD63). The apoptosis of podocytes was evaluated by flow cytometry, and the expression of apoptosis-associated proteins cleaved-caspase-3 and caspase-3 were determined by western blot analysis. Results: Deficient autophagy, which was evident by decreased LC3-II and CD63 levels, caused accumulation of p62, and fewer autophagosomes were observed in the MPC5 cells cultured with the IgAN supernatant, along with stronger expression of cleaved caspase-3 and a higher apoptosis rate. Inhibition of autophagy was alleviated in the IgANs+Rap group. The LC3-II/LC3-I ratio increased by almost 30%, the accumulated p62 amount was reduced by 50%, and the number of autophagosomes per podocyte increased to about 7 times that of the IgAN groups. These results were confirmed by immunofluorescence staining. In addition, the apoptosis rate of MPC5 cells decreased from 19.88% in the IgAN group to 16.78% in the IgANs+Rap group, which was accompanied by a weaker expression level of cleaved caspase-3. Conclusions: Rapamycin can reduce the apoptosis of podocytes by inducing autophagy in IgAN.

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“…9,10 Furthermore, the highly specialized and terminally differentiated podocytes are unable to proliferate, so autophagy plays an important role in maintaining the normal structure and function of podocytes. 11 Autophagic dysfunction is involved in the loss of the podocytes, resulting in a large amount of proteinuria in DN patients. 12 Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to the lysosome and then degraded.…”

Section: Introductionmentioning

confidence: 99%

<p>Curcumin Inhibited Podocyte Cell Apoptosis and Accelerated Cell Autophagy in Diabetic Nephropathy via Regulating Beclin1/UVRAG/Bcl2</p>

Zhang¹,

Fang²,

Zhang³

et al. 2020

DMSO

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Introduction: Curcumin has various biological properties including being antiinflammatory and antidiabetic. Podocyte apoptosis and autophagy dysfunction have been found to be responsible for the development of diabetic nephropathy (DN). Thus, the aim of the study was to investigate the effects of curcumin on the podocyte apoptosis and autophagy in DN and clarify its potential mechanisms. Methods: The mice with DN induced by injection of streptozotocin were treated with curcumin by gavage at a dose of 200 mg/kg/day for 8 weeks. The serum lipid levels were detected by total cholesterol (TC) and triglyceride (TG) kits at different time points. Renal damage was assessed by detecting urine albumin, serum creatinine (Scr), HE staining and PAS staining. The renal impairment was detected by immunohistochemical staining and TUNEL staining. Western blot assay tested the expression of autophagy-related and apoptotic-related proteins in vivo and vitro. The viabilities and apoptosis of MPC5 cells exposed to high glucose (HG) or curcumin were respectively detected by CCK-8 assay and flow cytometry. Results: The results showed that curcumin significantly decreased the progress of DN possibly via increasing autophagy and inhibiting apoptosis of renal cell in DN mice. Besides, podocyte marker proteins (podocalyxin and nephrin) were markedly increased in DN mice by curcumin treatment. The autophagy-related proteins LC3, p62, Beclin1, UVRAG and ATG5 were significantly affected in DN mice by curcumin, along with reducing expression of pro-apoptotic protein Bax and caspase-3 and increasing antiapoptotic protein Bcl-2. In vitro, curcumin increased the viabilities and inhibited apoptosis of MPC5 cells exposed to high glucose (HG). In addition, the podocyte autophagy was enhanced partly via regulating beclin1/UVRAG. Discussion: Together, the results showed that curcumin inhibited podocyte apoptosis and accelerated cell autophagy via regulating Beclin1/UVRAG/Bcl2. Thus, the study showed that curcumin exerted significantly protective effects in DN.

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Emerging role of podocyte autophagy in the progression of diabetic nephropathy

Cited by 83 publications

References 0 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

Rapamycin Induces Autophagy and Reduces the Apoptosis of Podocytes Under a Stimulated Condition of Immunoglobulin A Nephropathy

<p>Curcumin Inhibited Podocyte Cell Apoptosis and Accelerated Cell Autophagy in Diabetic Nephropathy via Regulating Beclin1/UVRAG/Bcl2</p>

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