Glycogen synthase kinase 3β hyperactivity in urinary exfoliated cells predicts progression of diabetic kidney disease

Liang, Xianhui; Wang, Pei; Chen, Bohan; Ge, Yan; Gong, Athena Y.; Flickinger, Bryce; Malhotra, Deepak; Wang, Li Juan; Dworkin, Lance D.; Liu, Zhangsuo; Gong, Rujun

doi:10.1016/j.kint.2019.08.036

Cited by 41 publications

(40 citation statements)

References 50 publications

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“…The most common clinical feature of DN is progressive proteinuria due to impairment of the GFB, and the normal morphology and function of podocytes play an important role in proteinuria formation and maintenance of renal function [ 14 , 15 ]. In many studies, podocytes have been treated with high glucose to cause DN in experimental models [ 16 , 17 ]. In this study, we treated podocytes with high glucose to construct a cell model of DN, and found that high glucose induced increased levels of inflammation and cell damage in podocytes.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 37 (IL-37) Reduces High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis of Podocytes by Inhibiting the STAT3–Cyclophilin A (CypA) Signaling Pathway

et al. 2020

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Background Diabetic nephropathy (DN), the formation of albuminuria, is one of the most important complications seen in diabetic patients. IL-37, an inhibitor of congenital inflammation and immune response, plays an important role in the occurrence and development of diabetes, but its study in DN has not been previously reported. Material/Methods Podocyte transfection techniques were used to overexpress STAT3 and cyclophilin A (CypA). The expression of IL-37, STAT3, and CypA was detected by RT-qPCR and western blot. Cell survival was detected by CCK-8. The expression of inflammatory factors and molecules related to oxidative stress was detected by ELISA and western blot, and cell apoptosis was detected by flow cytometry and western blot. Results The expression of IL-37 was significantly decreased in high glucose-treated podocytes. IL-37 improved the survival rate of podocytes suffering from high glucose-induced apoptosis. It inhibited the expression of the inflammation-related factors tumor necrosis factor α (TNF-α), IL-1β, IL-6, malondialdehyde (MDA), and lactate dehydrogenase (LDH), and promoted the expression of superoxide dismutase (SOD) in high glucose-treated podocytes. In addition, IL-37 inhibited the expression of the inflammation-related proteins MCP-1, NLRP3, ASC, and caspase-1. IL-37 also inhibited high glucose-induced apoptosis of podocytes by inhibiting the expression of the apoptosis-related proteins Bax and cleaved caspase-3/6/9, and by promoting the expression of Bcl-2. At the same time, we found that the STAT3/CypA signaling pathway was activated after induction by high glucose, while it was inhibited after treatment with IL-37. Overexpression of STAT3 and CypA inhibited the effects of IL-37 on the alleviation of inflammation and oxidative stress and on the reduction of apoptosis of high glucose-treated podocytes. Conclusions IL-37 can significantly reduce podocyte inflammation, oxidative stress, and apoptosis induced by high glucose, and can inhibit the STAT3-CypA signaling pathway. Upregulation of the STAT3-CypA signaling pathway can inhibit the protective effect of IL-37 against podocyte injury induced by high glucose.

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Section: Discussionmentioning

confidence: 99%

Interleukin 37 (IL-37) Reduces High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis of Podocytes by Inhibiting the STAT3–Cyclophilin A (CypA) Signaling Pathway

et al. 2020

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“…The results showed that p-AKT levels upregulated in DN were significantly decreased by geniposide ( Figure 6A), which correlates with activation of ULK1 to restore autophagy function. In addition, we investigated whether geniposide affects the GSK3β activity in DN, as previous studies report differential effects in the regulation of autophagy by GSK3β, and associated pathology in diabetic kidneys [44][45][46]. Our results showed that GSK3β was significantly activated by geniposide treatment in DN mice, as indicated by reduced levels of inactive p-GSK3β (Ser9); but there was no significant change in the levels of active p-GSKβ (Tyr216) ( Figure 6B).…”

Section: Geniposide Protected the Kidney Through Ampk Activation And mentioning

confidence: 55%

“…Activation of GSK3β also ameliorates renal injury in STZ-induced type 1 diabetes [45]. Conversely, renal expression and activity of GSK3β are amplified in urinary exfoliated cells and diabetic patients, where the activated form of GSK3β at Tyr216 was elevated, predicting the progression of DN [44]. In this study, we demonstrated that GSK3β was significantly activated by geniposide in DN mice, as indicated by reduced levels of inactive p-GSK3β (Ser9), but not being altered in the active p-GSK3β (Tyr216) levels ( Figure 6B).…”

Section: Discussionmentioning

confidence: 99%

Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

Dusabimana

Park

et al. 2021

IJMS

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Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.

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“…In addition, much higher level expression of GSK3β and phosphorylated form have linked to progression of albuminuria and diabetic kidney injury. Further analysis, renal glomeruli and tubules manifest higher phosphorylated GSK3β(Tyr216) [182] Since there are many comorbidities associated with diabetes, the function of GSK3β in kidney could be conceived with more attention during disease or therapy-related renal function interference [183,184]. Particularly, recent approach using detection of GSK3β activity in urinary exfoliated cells for early evaluation renal function in diabetic patients [182].…”

Section: Gsk3β In Renal Cellsmentioning

confidence: 99%

GSK3 modulation in acute lung injury, myocarditis and polycystic kidney disease-related aneurysm

Liu

Chiang

Kao

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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show abstract

Glycogen synthase kinase 3β hyperactivity in urinary exfoliated cells predicts progression of diabetic kidney disease

Cited by 41 publications

References 50 publications

Interleukin 37 (IL-37) Reduces High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis of Podocytes by Inhibiting the STAT3–Cyclophilin A (CypA) Signaling Pathway

Interleukin 37 (IL-37) Reduces High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis of Podocytes by Inhibiting the STAT3–Cyclophilin A (CypA) Signaling Pathway

Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

GSK3 modulation in acute lung injury, myocarditis and polycystic kidney disease-related aneurysm

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