Anti-inflammatory, antioxidant and renoprotective effects of SOCS1 mimetic peptide in the BTBR ob/ob mouse model of type 2 diabetes

IntroductionDiabetic nephropathy (DN) is the leading cause of chronic kidney disease worldwide. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway participates in the development and progression of DN. Among the different mechanisms involved in JAK/STAT negative regulation, the family of suppressor of cytokine signaling (SOCS) proteins has been proposed as a new target for DN. Our aim was to evaluate the effect of SOCS1 mimetic peptide in a mouse model of obesity and type 2 diabetes (T2D) with progressive DN.Research design and methodsSix-week-old BTBR (black and tan brachyuric) mice with the ob/ob (obese/obese) leptin-deficiency mutation were treated for 7 weeks with two different doses of active SOCS1 peptide (MiS1 2 and 4 µg/g body weight), using inactive mutant peptide (Mut 4 µg) and vehicle as control groups. At the end of the study, the animals were sacrificed to obtain blood, urine and kidney tissue for further analysis.ResultsTreatment of diabetic mice with active peptide significantly decreased urine albumin to creatinine ratio by up to 50%, reduced renal weight, glomerular and tubulointerstitial damage, and restored podocyte numbers. Kidneys from treated mice exhibited lower inflammatory infiltrate, proinflammatory gene expression and STAT activation. Concomitantly, active peptide administration modulated redox balance markers and reduced lipid peroxidation and cholesterol transporter gene expression in diabetic kidneys.ConclusionTargeting SOCS proteins by mimetic peptides to control JAK/STAT signaling pathway ameliorates albuminuria, morphological renal lesions, inflammation, oxidative stress and lipotoxicity, and could be a therapeutic approach to T2D kidney disease.

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Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis

Antioxidants ◽

10.3390/antiox9080754 ◽

2020 ◽

Vol 9 (8) ◽

pp. 754

Author(s):

Sara La Manna ◽

Laura Lopez-Sanz ◽

Susana Bernal ◽

Luna Jimenez-Castilla ◽

Ignacio Prieto ◽

...

Keyword(s):

Gene Expression ◽

Experimental Atherosclerosis ◽

Janus Kinase ◽

Cytokine Signaling ◽

Antioxidant Genes ◽

Antioxidant Agents ◽

Atheroma Plaque ◽

Socs Proteins

The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that KIR-SOCS1 mimetics can be considered valuable therapeutics in several disorders (e.g., diabetes, neurological disorders and atherosclerosis). Herein, we investigated the antioxidant and atheroprotective effects of PS5, a peptidomimetic of KIR-SOCS1, both in vitro (vascular smooth muscle cells and macrophages) and in vivo (atherosclerosis mouse model) by analyzing gene expression, intracellular O2•− production and atheroma plaque progression and composition. PS5 was revealed to be able to attenuate NADPH oxidase (NOX1 and NOX4) and pro-inflammatory gene expression, to upregulate antioxidant genes and to reduce atheroma plaque size, lipid content and monocyte/macrophage accumulation. These findings confirm that KIR-SOCS1-based drugs could be excellent antioxidant agents to contrast atherosclerosis.

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A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis

American Journal Of Pathology ◽

10.1016/j.ajpath.2017.10.012 ◽

2018 ◽

Vol 188 (2) ◽

pp. 343-352 ◽

Cited By ~ 4

Author(s):

Karin E. Bornfeldt ◽

Farah Kramer ◽

Anna Batorsky ◽

Jinkuk Choi ◽

Kelly L. Hudkins ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Mouse Model ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Diabetes Mouse

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Analysis of hepatic gene expression profile in a spontaneous mouse model of type 2 diabetes under a high sucrose diet

Endocrine Journal ◽

10.1507/endocrj.ej12-0258 ◽

2013 ◽

Vol 60 (3) ◽

pp. 261-274 ◽

Cited By ~ 28

Author(s):

Koji Nojima ◽

Ken Sugimoto ◽

Hironori Ueda ◽

Naru Babaya ◽

Hiroshi Ikegami ◽

...

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Mouse Model ◽

Gene Expression Profile ◽

Expression Profile ◽

Hepatic Gene Expression ◽

Sucrose Diet ◽

High Sucrose Diet ◽

High Sucrose

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Abstract #802036: Safety and Efficacy of Faster Acting Insulin Aspart in People With Type 2 Diabetes and Chronic Kidney Disease: A Real-World Study from India

Endocrine Practice ◽

10.1016/s1530-891x(20)39507-0 ◽

2020 ◽

Vol 26 ◽

pp. 101-102

Author(s):

Supratik Bhattacharyya

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Real World ◽

Insulin Aspart ◽

Safety And Efficacy ◽

Acting Insulin

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Abstract #289 Effect of Linagliptin on Cardiovascular and Kidney Outcomes in Patients with Type 2 Diabetes and Kidney Disease: Carmelina®

Endocrine Practice ◽

10.1016/s1530-891x(20)46633-9 ◽

2019 ◽

Vol 25 ◽

pp. 117-118

Author(s):

Robert Toto ◽

Vlado Perkovic ◽

Odd Erik Johansen ◽

Mark Cooper ◽

Julio Rosenstock ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease

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No effect of vitamin D supplementation on metabolic parameters but on lipids in patients with type 2 diabetes and chronic kidney disease

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000642 ◽

2020 ◽

pp. 1-10

Author(s):

Jiwoon Kim ◽

Ji Sun Nam ◽

Heejung Kim ◽

Hye Sun Lee ◽

Jung Eun Lee

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Vitamin D ◽

Kidney Disease ◽

Vitamin D Supplementation ◽

Lipid Profiles ◽

Metabolic Parameters ◽

Injection Group ◽

Different Doses

Abstract. Background/Aims: Trials on the effects of cholecalciferol supplementation in type 2 diabetes with chronic kidney disease patients were underexplored. Therefore, the aim of this study was to investigate the effects of two different doses of vitamin D supplementation on serum 25-hydroxyvitamin D [25(OH)D] concentrations and metabolic parameters in vitamin D-deficient Korean diabetes patients with chronic kidney disease. Methods: 92 patients completed this study: the placebo group (A, n = 33), the oral cholecalciferol 1,000 IU/day group (B, n = 34), or the single 200,000 IU injection group (C, n = 25, equivalent to 2,000 IU/day). 52% of the patients had less than 60 mL/min/1.73m2 of glomerular filtration rates. Laboratory test and pulse wave velocity were performed before and after supplementation. Results: After 12 weeks, serum 25(OH)D concentrations of the patients who received vitamin D supplementation were significantly increased (A, -2.4 ± 1.2 ng/mL vs. B, 10.7 ± 1.2 ng/mL vs. C, 14.6 ± 1.7 ng/mL; p < 0.001). In addition, the lipid profiles in the vitamin D injection group (C) showed a significant decrease in triglyceride and a rise in HDL cholesterol. However, the other parameters showed no differences. Conclusions: Our data indicated that two different doses and routes of vitamin D administration significantly and safely increased serum 25(OH)D concentrations in vitamin D-deficient diabetes patients with comorbid chronic kidney disease. In the group that received the higher vitamin D dose, the lipid profiles showed significant improvement, but there were no beneficial effects on other metabolic parameters.

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