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Updated: Jul 4, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Nox4-SH3YL1 complex is involved in diabetic nephropathy
Sae Rom Lee1, Hye Eun Lee1, Jung-Yeon Yoo1
1Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea.
Abstract:
Nox4-derived H2O2 generation plays an important role in the pathogenesis of chronic kidney diseases (CKDs) such as diabetic nephropathy (DN). Here, we showed that SH3 domain-containing Ysc84-like 1 (SH3YL1), a Nox4 cytosolic activator, regulated DN. Streptozotocin (STZ)-induced type Ⅰ diabetic models in SH3YL1 whole-body knockout (KO) mice and podocyte-specific SH3YL1 conditional KO (Nphs2-Cre/SH3YL1fl/fl) mice were established to investigate the function of SH3YL1 in DN. The expression of fibrosis markers and inflammatory cytokines, the generation of oxidative stress, and the loss of podocytes were suppressed in diabetic SH3YL1 KO and Nphs2-Cre/SH3YL1fl/fl mice, compared to diabetic control mice. To extrapolate the observations derived from diabetic mice to clinical implication, we measured the protein level of SH3YL1 in patients DN. In fact, the SH3YL1 level was increased in patients DN. Overall, the SH3YL1-Nox4 complex was identified to play an important role in renal inflammation and fibrosis, resulting in the development of DN.
Insights
SH3YL1 protein is crucial in diabetic kidney disease development. Inhibiting SH3YL1 in mouse models reduced fibrosis and inflammation, suggesting it as a therapeutic target for diabetic nephropathy.
Area of Science:
- Nephrology
- Molecular Biology
- Pathogenesis of Kidney Disease
Background:
- Oxidative stress from Nox4-derived hydrogen peroxide contributes to chronic kidney diseases (CKDs), including diabetic nephropathy (DN).
- SH3 domain-containing Ysc84-like 1 (SH3YL1) is identified as a cytosolic activator of Nox4.
Purpose of the Study:
- To investigate the role of SH3YL1 in the pathogenesis of diabetic nephropathy.
- To determine the therapeutic potential of targeting the SH3YL1-Nox4 interaction in DN.
Main Methods:
- Established streptozotocin-induced type 1 diabetic mouse models with whole-body SH3YL1 knockout (KO) and podocyte-specific SH3YL1 conditional KO (Nphs2-Cre/SH3YL1fl/fl).
- Assessed markers of fibrosis, inflammatory cytokines, oxidative stress, and podocyte loss in diabetic mice.
- Measured SH3YL1 protein levels in human DN patient samples.
Main Results:
- SH3YL1 knockout in mice significantly suppressed fibrosis markers, inflammatory cytokines, oxidative stress, and podocyte loss in diabetic conditions.
- Increased SH3YL1 protein levels were observed in patients with diabetic nephropathy.
- The SH3YL1-Nox4 complex was implicated in renal inflammation and fibrosis development.
Conclusions:
- SH3YL1 plays a critical role in the development of diabetic nephropathy through the Nox4 pathway.
- Targeting SH3YL1 may offer a novel therapeutic strategy for managing diabetic kidney disease.
