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SOCS2 overexpression alleviates diabetic nephropathy in rats by inhibiting the TLR4/NF-κB pathway
Suxia Yang1, Junwei Zhang1, Shiying Wang1
1Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, 475000, China.
Abstract:
Suppressor of cytokine signaling 2 (SOCS2) was reported to be involved in the development of Diabetic Nephropathy (DN). However, its underlying mechanism remains undefined. Western blot was carried out to determine the expressions of SOCS2, Toll-like receptors 4 (TLR4) and nuclear factor kappa B (NF-κB) pathway-related proteins in DN patients, streptozotocin (STZ)-induced DN rats and high glucose (HG)-stimulated podocytes. The effects of SOCS2 overexpression on renal injury, the inflammatory cytokines production, renal pathological changes, apoptosis and the TLR4/NF-κB pathway in DN rats or HG-stimulated podocytes were investigated. TLR4 antagonist TAK-242 and NF-κB inhibitor PDTC were used to confirm the functional mechanism of SOCS2 overexpression in HG-stimulated podocytes. SOCS2 was down-regulated, while TLR4 and NF-κB were up-regulated in renal tissues of DN patients and DN rats. Ad-SOCS2 infection alleviated STZ-induced renal injury and pathological changes and inhibited STZ-induced IL-6, IL-1β and MCP-1 generation and activation of the TLR4/NF-κB pathway in DN rats. SOCS2 overexpression attenuated apoptosis, suppressed the inflammatory cytokines expression, and inactivated the TLR4/NF-κB pathway in HG-stimulated podocytes. Suppression of the TLR4/NF-κB pathway enhanced the inhibitory effect of SOCS2 overexpression on apoptosis and inflammatory cytokines expressions in HG-stimulated podocytes. SOCS2 overexpression alleviated the development of DN by inhibiting the TLR4/NF-κB pathway, contributing to developing new therapeutic strategies against DN.
Insights
Suppressor of cytokine signaling 2 (SOCS2) is down-regulated in diabetic nephropathy (DN). Overexpressing SOCS2 inhibits the Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) pathway, reducing renal injury and inflammation in DN.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Diabetic nephropathy (DN) is a significant complication of diabetes.
- The role of Suppressor of cytokine signaling 2 (SOCS2) in DN pathogenesis is not fully understood.
- Inflammation and podocyte injury are key features of DN, often involving the Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) pathway.
Purpose of the Study:
- To investigate the expression levels of SOCS2, TLR4, and NF-κB pathway proteins in DN.
- To elucidate the mechanism by which SOCS2 influences renal injury, inflammation, and apoptosis in DN.
- To evaluate the therapeutic potential of SOCS2 in mitigating DN progression.
Main Methods:
- Western blot analysis was used to assess protein expression in DN patients, STZ-induced DN rats, and high glucose-stimulated podocytes.
- Adenovirus-mediated SOCS2 (Ad-SOCS2) overexpression was employed in vivo and in vitro models.
- TLR4 antagonist (TAK-242) and NF-κB inhibitor (PDTC) were used to confirm pathway involvement.
Main Results:
- SOCS2 expression was decreased, while TLR4 and NF-κB pathway proteins were increased in DN renal tissues.
- SOCS2 overexpression ameliorated STZ-induced renal injury, pathological changes, and inflammatory cytokine production (IL-6, IL-1β, MCP-1) in rats.
- In HG-stimulated podocytes, SOCS2 overexpression reduced apoptosis, suppressed inflammation, and inactivated the TLR4/NF-κB pathway.
Conclusions:
- SOCS2 plays a protective role in diabetic nephropathy by inhibiting the TLR4/NF-κB signaling pathway.
- SOCS2 overexpression mitigates renal injury, inflammation, and apoptosis, suggesting its potential as a therapeutic target for DN.
- Targeting the SOCS2/TLR4/NF-κB axis offers a promising strategy for novel DN therapeutic interventions.
