Journal
BMJ OPEN DIABETES RESEARCH & CARE
Volume 8, Issue 1, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/bmjdrc-2020-001242
Keywords
albuminuria; inflammation and oxidative stress; type 2 diabetes; lipotoxicity
Categories
Funding
- Fondecyt [1160465, 21150768]
- Division of Nephrology, Universidad Austral de Chile
- Spanish Ministry of Economy and Competitiveness (MINECO/FEDER) [SAF2015-63696-R]
- Ministry of Science, Innovation and Universities (MICINN/FEDER) [RTI2018-098788-B-I00]
- Instituto de Salud Carlos III (FIS/FEDER) [PI17/01495, DTS-2017/00203, DTS19/00093]
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Introduction Diabetic 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 methods Six-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 mu g/g body weight), using inactive mutant peptide (Mut 4 mu g) 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. Results Treatment 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. Conclusion Targeting 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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