SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence

Related Experiment Videos

Sifang Zhang1, Guangyan Cai, Bo Fu

  • 1Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, People's Republic of China.

Mechanisms of Ageing and Development
|May 8, 2012
PubMed

Insights

High glucose accelerates kidney cell senescence by altering mTOR and SIRT1. Restoring SIRT1 activity, potentially via rapamycin, may counteract this process, offering insights into diabetic nephropathy treatment.

Area of Science:

  • Nephrology
  • Cell Biology
  • Biochemistry

Background:

  • Mammalian target of rapamycin (mTOR) deregulation is implicated in chronic kidney disease (CKD), including diabetic nephropathy.
  • Sirtuin 1 (SIRT1) plays a protective role in renal cells against aging and stress.
  • The interplay between mTOR and SIRT1 in high glucose-induced mesangial cell (MC) senescence is not fully understood.

Purpose of the Study:

  • To investigate the functional relationship between mTOR and SIRT1 in high glucose-induced MC senescence.
  • To explore the role of SIRT1 in mediating the effects of rapamycin on MC senescence.

Main Methods:

  • Cultured human mesangial cells exposed to high glucose conditions.
  • Manipulated mTOR and SIRT1 expression and activity using pharmacological agents (nicotinamide, NAD, resveratrol, rapamycin) and genetic tools (siRNA-SIRT1).
  • Assessed MC senescence markers and protein expression/activity levels.

Main Results:

  • High glucose increased mTOR and decreased SIRT1 expression and activity in MCs.
  • SIRT1 inhibition (siRNA-SIRT1, nicotinamide) promoted MC senescence, while NAD or resveratrol attenuated it.
  • Rapamycin inhibited high glucose-induced MC senescence and increased SIRT1 expression/activity.
  • SIRT1 inhibition blocked the protective effects of NAD, resveratrol, and rapamycin against MC senescence.

Conclusions:

  • SIRT1 is crucial for mediating the anti-senescence effects of rapamycin, NAD, and resveratrol in high glucose-treated MCs.
  • The findings suggest a critical role for SIRT1 in regulating MC senescence in the context of high glucose, relevant to diabetic nephropathy.

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Replicative Cell Senescence02:15

Replicative Cell Senescence

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds the telomeric...