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Abstract
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 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.
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.
- albuminuria
- inflammation and oxidative stress
- type 2 diabetes
- lipotoxicity
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Footnotes
JE, CG-G and SM are joint senior authors.
JE, CG-G and SM contributed equally.
Contributors LO-R contributed to the conception, design and performance of the experiments, acquisition, analysis and interpretation of all data, and drafting of the manuscript. YSM contributed to performance of the experiments and acquisition and analysis of data. RRR-D contributed to performance of the experiments and acquisition of data. DC contributed to analysis and interpretation of data. AD contributed to design and performance of the experiments. JE contributed to interpretation of data, drafting and critical review of the manuscript, and in securing financial support for the study. CG-G contributed to conception, design and performance of the experiments, analysis and interpretation of data, drafting of the manuscript, and in securing financial support for the study. SM contributed to interpretation of data, critical review of the manuscript and in securing financial support for the study. All authors reviewed the manuscript and approved the final version to be published. SM is the guarantor of this work and as such had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by grants Fondecyt Project N° 1160465 (to SM) and PhD Grant N° 21150768 (to LO-R), Division of Nephrology, Universidad Austral de Chile, the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER; SAF2015-63696-R, to CG-G), the Ministry of Science, Innovation and Universities (MICINN/FEDER; RTI2018-098788-B-I00, to CG-G), and Instituto de Salud Carlos III (FIS/FEDER; PI17/01495, DTS-2017/00203 and DTS19/00093, to JE).
Competing interests JE and CG-G are inventors on a patent application regarding clinical utility of SOCS peptide.
Patient consent for publication Not required.
Ethics approval The experimental protocol was reviewed and approved by the Ethics Committee for Animal Experiments of the University Austral of Chile (Permit N° 222–2015) according to the National Institutes of Health guidelines.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. The data sets and resources generated during the current study are available from the corresponding author upon reasonable request.