Overexpression of Sirtuin 3 in Obesity-Induced Chronic Kidney Disease Mice Model

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BODY-Background: Obesity and metabolic syndrome are independent risk factors for chronic kidney disease (CKD). Obesity-induced CKD is characterized by a progressive decline of the renal function and the development of tubulointerstitial fibrosis. Recently, studies showing ectopic lipid depositions in proximal tubular cells have emerged along with mitochondria dysfunction, suggesting a lipotoxicity in these cells. However, molecular mechanisms underlying these processes are still unclear. Our study will focus on the involvement of sirtuin 3 (SIRT3), a NAD+dependent deacetylase, in the ectopic lipid accumulation in kidney cells leading to CKD. SIRT3, mainly expressed in mitochondria, is known to play a critical role in metabolic responses and mitochondria functions. BODY-Methods: Male C57BL/6 WT and SIRT3 transgenic mice were assigned either to a low fat diet (LFD) or a high fat diet (HFD) for 20 weeks. At the end of the protocol, urine, blood and kidney samples were collected. Kidney function was investigated and morphological analyses were performed. BODY-Results: Wild-Type HFD mice presented renal hypertrophy and impaired renal function as attested by an increased albuminuria and proteinuria. Evidence of proximal tubule injury was observed in these mice with the presence of enlarged lipid vacuoles. In addition, these alterations were associated with the reduction of AMPK activity and the decrease in the relative mRNA and protein expression of SIRT3. Interestingly, renal hypertrophy and impaired renal function were significantly improved in SIRT3 transgenic mice fed a HFD. This was also associated with a reduced number and size of ectopic lipid vacuoles in proximal tubular cells. BODY-Conclusion: These findings reveal that SIRT3 plays a critical role in ectopic lipid accumulation in proximal tubular cells and impairment of renal function. Systemic overexpression of SIRT3 normalizes the renal alterations observed in HFD WT mice and may thus be a potential strategy to improve altered lipid metabolism in HFD-induced CKD.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.