Statin Improves Early-Phase Obesity-Induced Renal Injury via Restoring Autophagy Failure Through Rho/Rho Kinase/mTOR Pathway Inhibition

Obesity-induced renal injury serves as a preceding phase to the majority of diabetic nephropathy. We investigated the cascading pathophysiology of renal dysfunction induced by obesity and, as a result, identified the significant role of disrupted autophagy within the proximal tubular cells. In mice subjected to obesity induction through a high-fat diet, we observed weight gain, increased adipose tissue mass, decreased glucose tolerance, and insulin resistance, accompanied by the expression of albuminuria. This was further associated with glomerular hypertrophy and tubular epithelial cell enlargement. Among the histological changes, the most prominent was the enlargement of tubular epithelial cells, within which we witnessed substantial lipid accumulation in lysosomes. This observation indicated signs of autophagy dysfunction, raising the possibility that mTOR-mediated autophagy impairment in obesity could be a significant factor in renal function deterioration. Therapeutic intervention with statins, inhibiting the Rho/Rho kinase, simultaneously suppressed the Rho and mTOR cascades, ameliorating autophagy dysfunction. This intervention led to histological improvements and a reduction in albuminuria. The potential of statins to ameliorate changes in tubular and glomerular structures induced by obesity became evident, suggesting their viability as an effective therapeutic strategy for obesity- induced renal injury.