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

Abstract

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.

Nephroprotective Effects of Synthetic Flavonoid Hidrosmin in Experimental Diabetic Nephropathy

“…Dysregulated activation/expression of NF-κB, JAK/STAT, and their target genes have been detected in kidney biopsies from diabetic patients [ 8 , 55 ]. In experimental models, either gene deficiency or pharmacological inactivation of different family members (e.g., JAK2, STAT1, and STAT3) further implicates both pathways in DM and its chronic complications [ 56 , 57 ]. This study indicates that the renoprotective effects of hidrosmin in diabetic kidneys are mediated by the concerted inhibition of NF-κBp65 and STAT3 transcription factors, although further studies are needed to identify the exact mechanism of the compound.…”

Toll-Like Receptors in Acute Kidney Injury

“…In a murine model of cisplatin-induced AKI, SOCS1 expression was decreased, whereas induction of Jak2/STAT1 pathway with an AMPK activator restored SOCS1 levels and promoted renal protection [ 120 ]. Additionally, SOCS1-targeted therapy limited progression of diabetic nephropathy [ 121 , 122 , 123 ].…”

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

“…This synthetic, cell‐penetrating peptide derives from the KIR domain of SOCS1 that specifically binds to JAK autophosphorylation site and inhibits JAK1/2 and TYK2 kinase activity (Jager et al, 2011). In previous studies, we have determined the structure, pharmacokinetic parameters and effectiveness of S1 in different models (Opazo‐Ríos et al, 2020; Recio et al, 2014; Recio et al, 2017). The macroscopic biodistribution of fluorescent S1 peptide in elastase‐infused mice was evaluated by both in vivo and ex vivo imaging system.…”

“…S1 peptide mimics of the unique SOCS1 KIR domain, is conjugated to a hydrophobic sequence and effectively enters into the cells to suppress JAK kinase activity and STAT activation (Jager et al, 2011; Recio et al, 2014). So far, the in vivo anti‐inflammatory effects of different SOCS1 derived sequences have been investigated in preclinical models of inflammatory diseases (Ahmed, Larkin, & Johnson, 2015; Jager et al, 2011; La Manna et al, 2020; Madonna et al, 2013) and diabetic complications (Lopez‐Sanz et al, 2018; Opazo‐Ríos et al, 2020; Recio et al, 2014; Recio et al, 2017). Herein, we demonstrate that S1 therapy suppresses STAT1/3 and downstream target genes in aorta and prevents elastase‐induced AAA formation.…”