Abstract
Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). IRS-1 is also a substrate for different peptides and growth factors, and a transgenic mouse "knockout" for this protein does not have normal growth. However, the role of IRS-1 in kidney hypertrophy and/or hyperplasia was not investigated. In the present study we investigated IRS-1 protein and tyrosine phosphorylation levels in the remnant kidney after unilateral nephrectomy (UNX) in 6-week-old male Wistar rats. After insulin stimulation the levels of insulin receptor and IRS-1 tyrosine phosphorylation were reduced to 79 +/- 5% (P < 0.005) and 58 +/- 6% (P < 0.0001), respectively, of the control (C) levels, in the remnant kidney. It is possible that a circulating factor and/or a local (paracrine) factor playing a role in kidney growth can influence the early steps of insulin action in parallel. To investigate the hypothesis of a circulating factor, we studied the early steps of insulin action in liver and muscle of unilateral nephrectomized rats. There was no change in pp185 tyrosine phosphorylation levels in liver (C 100 +/- 12% vs UNX 89 +/- 9%, NS) and muscle (C 100 +/- 22% vs UNX 91 +/- 17%, NS), and also there was no change in IRS-1 phosphorylation levels in both tissues. These data demonstrate that after unilateral nephrectomy there is a decrease in insulin-induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle. It will be of interest to investigate which factors, probably paracrine ones, regulate these early steps of insulin action in the contralateral kidney of unilaterally nephrectomized rats.
Highlights
Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1)
One of the earliest cellular responses to stimulation by insulin is the activation of insulin receptor kinase and tyrosine phosphorylation of insulin receptor ß subunit and pp185, a cytoplasmic phosphoprotein found in most cells and tissues [1]
The cloned protein was called insulin receptor substrate 1 (IRS-1). This insulin receptor substrate is a cytoplasmic protein that is rapidly phosphorylated at a specific tyrosine after insulin stimulation and is important in mediating the metabolic and growth-promoting effects of this hormone
Summary
Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). This insulin receptor substrate is a cytoplasmic protein that is rapidly phosphorylated at a specific tyrosine after insulin stimulation and is important in mediating the metabolic and growth-promoting effects of this hormone. The first aim of this study was to investigate IRS-1 protein and tyrosine phosphorylation levels in the remnant kidney after UNX.
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