Insulin-like growth factors inhibit podocyte apoptosis through the PI3 kinase pathway

Darren J Bridgewater1, Jackie Ho, Victor Sauro

  • 1Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.

Kidney International
|March 23, 2005
PubMed
Abstract

Insights

Insulin-like growth factor-1 (IGF-1) protects fetal podocytes from apoptosis by activating the phosphatidylinositol 3-kinase (PI3K) pathway. This finding suggests IGF-1 may help treat progressive kidney diseases.

Area of Science:

  • Nephrology
  • Cell Biology
  • Endocrinology

Background:

  • Podocyte injury is central to many kidney diseases.
  • Understanding factors regulating podocyte survival is crucial.

Purpose of the Study:

  • To investigate the role of the insulin-like growth factor (IGF) system in fetal podocyte survival.
  • To elucidate the signaling pathways involved in IGF-mediated protection.

Main Methods:

  • Human fetal podocytes were induced to undergo apoptosis using etoposide.
  • Apoptosis was measured by DNA fragmentation and nuclear morphology.
  • The effect of IGF-1 and PI3K pathway inhibitors was assessed.

Main Results:

  • Etoposide significantly increased podocyte apoptosis.
  • IGF-1 reduced apoptosis to control levels.
  • IGF-1 protection was mediated by the PI3K/AKT/PKB pathway, involving IRS-1, p85, and bad.

Conclusions:

  • The IGF system plays a vital role in fetal podocyte survival in vitro.
  • IGF-1 may offer a therapeutic strategy to mitigate podocyte loss in progressive renal diseases.

Related Concept Videos

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...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released...
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...