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Insulin receptor substrate‐2 is expressed in kidney epithelium and up‐regulated in diabetic nephropathy
Author(s) -
Hookham Michelle B.,
O'Donovan Helen C.,
Church Rachel H.,
MercierZuber Annie,
Luzi Lucilla,
Curran Simon P.,
Carew Rosemarie M.,
Droguett Alejandra,
Mezzano Sergio,
Schubert Markus,
White Morris F.,
Crean John K.,
Brazil Derek P.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12305
Subject(s) - medicine , endocrinology , kidney , diabetic nephropathy , kidney development , biology , insulin , kidney disease , insulin receptor , insulin resistance , biochemistry , embryonic stem cell , gene
Diabetic nephropathy ( DN ) is a progressive fibrotic condition that may lead to end‐stage renal disease and kidney failure. Transforming growth factor‐β1 and bone morphogenetic protein‐7 ( BMP 7) have been shown to induce DN ‐like changes in the kidney and protect the kidney from such changes, respectively. Recent data identified insulin action at the level of the nephron as a crucial factor in the development and progression of DN . Insulin requires a family of insulin receptor substrate ( IRS ) proteins for its physiological effects, and many reports have highlighted the role of insulin and IRS proteins in kidney physiology and disease. Here, we observed IRS 2 expression predominantly in the developing and adult kidney epithelium in mouse and human. BMP 7 treatment of human kidney proximal tubule epithelial cells ( HK ‐2 cells) increases IRS 2 transcription. In addition, BMP 7 treatment of HK ‐2 cells induces an electrophoretic shift in IRS 2 migration on SDS / PAGE , and increased association with phosphatidylinositol‐3‐kinase, probably due to increased tyrosine/serine phosphorylation. In a cohort of DN patients with a range of chronic kidney disease severity, IRS 2 m RNA levels were elevated approximately ninefold, with the majority of IRS 2 staining evident in the kidney tubules in DN patients. These data show that IRS 2 is expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP 7 in the kidney. The specific up‐regulation of IRS 2 in the kidney tubules of DN patients also indicates a novel role for IRS 2 as a marker and/or mediator of human DN progression. Structured digital abstractIRS2 physically interacts with p85α by anti bait coimmunoprecipitation ( View interaction )