The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells

Abstract

The kidney is one of the fastest-aging organs, and renal senescence has become a major disease affecting human health. Renal cellular senescence is regulated by the joint action of multiple signal transduction pathways. The previous study by our research group found that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was involved in angiotensin II (Ang II)-induced senescence of human glomerular mesangial cells. However, the unique role of STAT3 activation in Ang II-induced senescence of human glomerular mesangial cells and the underlying mechanisms remain unclear. The present study revealed that Ang II induced premature senescence, promoted autophagy and activated oxidative stress responses in human glomerular mesangial cells. Autophagy mediates the senescence-inducing effect of Ang II on human glomerular mesangial cells. Inhibition of oxidative stress with N-acetylcysteine (NAC) or interference with STAT3/mechanistic target of rapamycin (mTOR) activity with S3I-201 or STAT3-siRNA suppressed autophagy to a certain extent, which was conducive to delaying the senescence of glomerular mesangial cells. The antioxidant probucol reduced autophagy in human glomerular mesangial cells and alleviated the aging process of these cells by regulating STAT3/mTOR. These findings identify a role of STAT3/mTOR-regulated autophagy in Ang II-induced senescence of human glomerular mesangial cells and may provide a theoretical basis for anti-senescence treatment in clinical practice.

Keywords: Angiotensin II; Autophagy; Kidney; STAT3; Senescence; mTOR.