Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance
Yu B Y Sun1, Xinli Qu1, Victor Howard2
1Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
Abstract:
Signaling by TGF-β/Smad3 plays a key role in renal fibrosis. As obesity is one of the major risk factors of chronic and end-stage renal disease, we studied the role of Smad3 signaling in the pathogenesis of obesity-related renal disease. After switching to a high fat diet, the onset of Smad3 C-terminal phosphorylation, increase in albuminuria, and the early stages of peripheral and renal insulin resistance occurred at 1 day, and 4 and 8 weeks, respectively, in C57BL/6 mice. The loss of synaptopodin, a functional marker of podocytes, and phosphorylation of the Smad3 linker region (T179 and S213) appeared after 4 weeks of the high fat diet. This suggests a temporal pattern of Smad3 signaling activation leading to kidney injury and subsequent insulin resistance in the development of obesity-related renal disease. In vivo, Smad3 knockout attenuated the high fat diet-induced proteinuria, renal fibrosis, overall podocyte injury, and mitochondrial dysfunction in podocytes. In vitro palmitate caused a rapid activation of Smad3 in 30 min, loss of synaptopodin in 2 days, and impaired insulin signaling in 3 days in isolated mouse podocytes. Blockade of either Smad3 phosphorylation by SIS3 (a Smad3 inhibitor) or T179 phosphorylation by flavopiridol (a CDK9 inhibitor) prevented the palmitate-induced loss of synaptopodin and mitochondrial function in podocytes. Thus, Smad3 signaling plays essential roles in obesity-related renal disease and may be a novel therapeutic target.
Insights
Obesity-related kidney disease involves Smad3 signaling. Inhibiting Smad3 activation in podocytes protects against high-fat diet-induced kidney injury and insulin resistance, suggesting Smad3 as a therapeutic target.
Area of Science:
- Nephrology
- Metabolic Disorders
- Cellular Signaling
Background:
- Obesity is a major risk factor for chronic kidney disease.
- Transforming growth factor-beta (TGF-β)/Smad3 signaling is implicated in renal fibrosis.
- The specific role of Smad3 in obesity-related kidney disease pathogenesis requires elucidation.
Purpose of the Study:
- To investigate the role of Smad3 signaling in the development of obesity-related renal disease.
- To determine the temporal activation pattern of Smad3 signaling in response to a high-fat diet.
- To evaluate Smad3 as a potential therapeutic target for obesity-induced kidney complications.
Main Methods:
- Utilized C57BL/6 mice fed a high-fat diet to model obesity-related renal disease.
- Assessed Smad3 C-terminal and linker region phosphorylation, albuminuria, podocyte injury markers (synaptopodin), and insulin resistance.
- Employed Smad3 knockout mice and in vitro podocyte cultures treated with palmitate, Smad3 inhibitors (SIS3), and CDK9 inhibitors (flavopiridol).
Main Results:
- High-fat diet induced Smad3 phosphorylation, albuminuria, podocyte injury, and insulin resistance in mice.
- Smad3 knockout attenuated high-fat diet-induced kidney damage, proteinuria, fibrosis, and mitochondrial dysfunction.
- In vitro, palmitate activated Smad3, caused synaptopodin loss, and impaired insulin signaling in podocytes; Smad3 inhibition protected podocyte function.
Conclusions:
- Smad3 signaling is critically involved in the pathogenesis of obesity-related renal disease.
- Temporal activation of Smad3 signaling precedes kidney injury and insulin resistance.
- Targeting Smad3 phosphorylation presents a promising therapeutic strategy for obesity-induced kidney disease.
