TISSUE-SPECIFIC REGULATION OF IRS-1 IN UNILATERALLY NEPHRECTOMIZED RATS

Insulin stimulates the tyrosine kinase activity of its receptor, resul ting in the phosphorylation of its cytosolic substrate, insulin recept or substrate 1 (IRS-1). IRS-1 is also a substrate for different peptid es and growth factors, and a transgenic mouse ''knockout'' for this pr otein does not have normal growth. However, the role of IRS-1 in kidne y hypertrophy and/or hyperplasia was not investigated. In the present study we investigated IRS-1 protein and tyrosine phosphorylation level s in the remnant kidney after unilateral nephrectomy (UNX) in 6-week-o ld male Wistar rats. After insulin stimulation the levels of insulin r eceptor and IRS-1 tyrosine phosphorylation were reduced to 79 +/- 5% ( P<0.005) and 58 +/- 6% (P<0.0001), respectively, of the control (C) le vels, 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 investigat e the hypothesis of a circulating factor, we studied the early steps o f insulin action in liver and muscle of unilateral nephrectomized rats . There was no change in pp185 tyrosine phosphorylation levels in live r (C 100 +/- 12% vs UNX 89 +/- 9%, NS) and muscle (C 100 +/- 22% vs UN X 91 +/- 17%, NS), and also there was no change in IRS-1 phosphorylati on levels in both tissues. These data demonstrate that after unilatera l nephrectomy there is a decrease in insulin-induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver a nd muscle. It will be of interest to investigate which factors, probab ly paracrine ones, regulate these early steps of insulin action in the contralateral kidney of unilaterally nephrectomized rats.