High expression of PKC-MAPK pathway mRNAs correlates with glomerular lesions in human diabetic nephropathy

Abstract

High expression of PKC-MAPK pathway mRNAs correlates with glomerular lesions in human diabetic nephropathy.BackgroundActivation of protein kinase C (PKC) is a major signaling pathway for transforming growth factor (TGF)-β to induce extracellular matrix (ECM) production in diabetic nephropathy (DN). PKC also activates mitogen-activated protein kinase (MAPK), which is called the PKC-MAPK pathway. The PKC-MAPK pathway is probably responsible for PKC-related abnormalities in diabetic glomeruli. To confirm the involvement of this pathway, we determined the localization and expression of mRNAs in glomeruli by in situ hybridization method.MethodsIn the present study, we examined expression of PKCβ1, MAPK/ERK kinase (MEK) 1, MEK2, extracellular signal-regulated protein kinase (ERK) 1, ERK2, and TGF-β1 mRNAs using renal tissue samples from kidneys affected by DN (N = 21) and from normal human kidney (NHK; N = 6). We also performed an immunohistochemical study using anti-phosphorylated MEK1/2 (P-MEK) and ERK1/2 (P-ERK) antibodies. The glomerular severity of DN was classified into three groups according to mesangial expansion: D1 (N = 4), D2 (N = 13), and D3 (N = 4). We analyzed differences and correlations between variables.ResultsIn the glomeruli, the number of cells that stained for these mRNAs in DN was significantly higher than in NHK. The expression of PKC-MAPK pathway mRNAs tended to be inversely proportional to the degree of mesangial expansion. The P-MEK and P-ERK signal intensity were parallel to its mRNA expression pattern. Furthermore, there were significant correlations among the P-MEK, P-ERK signal intensity, PKCβ1 mRNA expression.ConclusionOur results suggest that high expression of PKC-MAPK pathway mRNAs plays an important role in the development and/or progression of early tissue damage in DN