mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN

Area of Science:

• Nephrology
• Virology
• Molecular Biology

Background:

• Oxidative stress contributes to kidney cell injury in HIV-associated nephropathy (HIVAN).
• The role of p53, a key oxidative stress modulator, in HIVAN pathogenesis is unclear.
• The mammalian target of rapamycin (mTOR) pathway's involvement in p53-mediated kidney injury in HIVAN requires investigation.

Purpose of the Study:

• To investigate the role of the mTOR pathway in p53-mediated oxidative kidney cell injury in HIVAN.
• To evaluate the therapeutic potential of mTOR inhibition in mitigating HIVAN.

Main Methods:

• In vivo studies using Tg26 mice (a model for HIVAN) treated with an mTOR inhibitor (rapamycin).
• In vitro studies using HIV-infected podocytes (HP/HIV) with and without mTOR inhibition or silencing.
• Assessment of p53 expression, downstream signaling, oxidative stress markers (8-hydroxy deoxyguanosine), apoptosis, and kidney histology.

Main Results:

• mTOR inhibition downregulated renal p53 expression and associated signaling in Tg26 mice.
• Rapamycin treatment reduced glomerulosclerosis, tubular microcysts, and apoptosis in HIVAN mouse models.
• mTOR inhibition attenuated p66ShcA expression, enhanced antioxidant enzymes (MnSOD, catalase), and protected against podocyte apoptosis in vitro.
• Silencing mTOR in HP/HIV cells prevented p53 activation and reduced podocyte apoptosis.

Conclusions:

• The mTOR pathway is critical for p53 activation and subsequent oxidative kidney cell injury in the context of HIVAN.
• mTOR inhibition demonstrates a protective effect against HIVAN by downregulating p53 and oxidative stress.
• Targeting the mTOR pathway represents a potential therapeutic strategy for managing HIVAN.