Abstract 11021: Akt1-mediated Skeletal Muscle Growth Attenuates Renal Interstitial Fibrosis and Inflammation in Obstructive Nephropathy
Introduction: Muscle wasting is a common complication in chronic kidney disease (CKD), and contributes to poor outcomes. It is unknown whether the reverse is true; will an increase in lean muscle mass can improve renal damages in the setting of CKD?
Hypothesis: Skeletal muscle growth attenuates pathological renal damages after mouse model of CKD.
Methods: We utilized skeletal muscle-specific, conditional Akt1 transgenic mice, that can induce the growth of functional skeletal muscle by switching Akt1 signaling on in muscle fibers. Seven days after Akt1 activation in skeletal muscle, renal injury was induced by unilateral ureteral obstruction (UUO) in Akt1 transgenic and wild type (WT) mice. Renal damages were examined by histological and gene expression analysis at 3, 7 and 14 days after UUO.
Results: Activation of Akt1 signaling in myofibers led to an increase in skeletal muscle mass, assessed by gastrocnemius muscle weight/tibial length ratio, at 7 and 14 days after surgery (15.0 vs. 9.5 mg/mm; p<0.001, 12.5 vs. 8.8 mg/mm; p<0.001, respectively). Masson's trichrome and PAS stained histological sections showed that renal interstitial fibrosis and tubular injury was dramatically increased by UUO in WT mice, but these changes were attenuated in Akt1 transgenic mice at 14 days after surgery. Upregulation of inflammatory-related gene expression, including monocyte chemoattractant protein 1, interleukin 1β, and macrophage marker F4/80, were significantly decreased in Akt1 transgenic mice compared to WT mice. Akt1-mediated skeletal muscle growth also attenuated fibrosis-related genes expression, such as connective tissue growth factor, type I and III collagen, although transforming growth factor-β expression was unaltered. Attenuated renal damages in Akt1 transgenic mice were accompanied by AMP kinase activation, which is known as renal protective signaling. On the other hand, ERK activation was decreased in Akt1 transgenic mice compared to WT mice in kidney.
Conclusions: Akt1-mediated skeletal muscle growth attenuates renal interstitial fibrosis and inflammation after UUO, suggesting clinical utility of exercise lead to a skeletal muscle growth, such as resistance training in kidney diseases.
- © 2012 by American Heart Association, Inc.