05). However, L-carnitine treatment had no effect. Buparlisib While SE offspring are glucose intolerant, SE+L-C offspring showed more normalized glucose tolerance compared to control. Conclusion: L-carnitine supplement during gestation and lactation has no effect on renal underdevelopment but improve glucose intolerance in female offspring induced by maternal SE. 155 THE ESSENTIAL ROLE OF SMAD3 SIGNALLING IN THE DEVELOPMENT OF PODOCYTE INJURY IN A MOUSE MODEL OF DIET-INDUCED OBESITY Y SUN, X QU, V HOWARD, M SLEEMAN, J LI Monash University, Clayton, Victoria, Australia

Aim: This study examined the role of Smad3 in the development of renal injury in a mouse model of high fat diet (HFD)-induced obesity. Background: Central obesity is associated with the metabolic syndrome and poses an increased risk for the development of renal-cardiovascular diseases and type 2 diabetes. TGF-β/Smad signalling plays a key role in renal fibrosis with the majority of the biological effects through Smad3. Smad3-null mice are protected from HFD-induced obesity and exhibit reduced adiposity. We hypothesize that Smad3 deficiency may reduce obesity-related kidney fibrosis. Methods: Smad3 wild type and knockout mice were given HFD or normal diet (ND). Mice were killed

8 or 16 weeks after HFD or ND treatment. Results: In response to a HFD, we have observed activation https://www.selleckchem.com/products/Dasatinib.html of Smad3, Metalloexopeptidase a significant increase of albuminuria and the incipience of insulin resistance occur at 1, 4 and 6 week(s) respectively. This suggests a temporal pattern of Smad3 signalling activation leading to kidney injury and subsequent insulin resistance in the aetiology of obesity-related kidney disease. With prolonged HFD exposure (16 weeks), there is a progressive increase of renal fibrosis associated with loss

of synaptopodin expression. Smad3 deficiency attenuated HFD-induced proteinuria and glomerulosclerosis, modified macrophages from M1 to M2-type, and prevented down-regulation of synaptopodin. In in vitro model, palmitate acid addition to cultured podocytes induced a similar rapid activation of Smad3 and loss of synaptopodin after 5 days treatment. Addition of the specific Smad3 inhibitor, SIS3, prevented palmitate-induced down-regulation of synaptopodin expression. Conclusions: Our studies provide the first evidence that Smad3 plays essential roles in HFD-induced podocyte damage by down-regulation of synaptopodin. Smad3 may be a novel therapeutic target in obesity-related kidney disease. Subheadings: Smad3 in obesity-related kidney disease.