Effect of Smad pathway activation on podocyte cell cycle regulation: An immunohistochemical evaluation

Abstract

Background: Mature podocytes are in cell cycle arrest and their inability to proliferate successfully is a consequence of negative cell-cycle regulators' expression, such as p57. Phosphorylated smad2/smad3 (pSmad2/3) is an intracellular heteromeric mediator of transforming growth factor beta (TGF-β) signals and, together with co-activators such as P300, regulates gene transcription, including cell cycle regulator proteins. Methods: In order to investigate Smad pathway activation and podocyte cell cycle regulation in glomerular injury, we studied the glomerular immunohistochemical expression of p57, pSmad2/3 and P300 in samples from 67 patients with various types of glomerulonephritis (GN) and 10 normal kidney tissue specimens. Results: pSmad2/3 and p300 expression were found significantly increased in all glomerular cell types in both proliferative and nonproliferative GN, while a significant reduction in p57-positive podocytes was observed when compared to controls. Staining for p57 was found to inversely correlate to pSmad2/3 suggesting that glomerular Smad pathway activation is related to down-regulation of p57 expression in proliferative glomerulonephritis. To our knowledge, this is the first study that indicates a relation between the TGF-beta/Smad signalling pathway and the cell cycle regulatory protein p57 in human GN. Conclusion: The increased pSmad2/3 staining together with the reduced p57 expression found in biopsy specimens with intense interstitial inflammation, indicate a possible relation between interstitial inflammation, glomerular Smad pathway activation and podocyte cell-cycle deregulation. © 2014 Informa Healthcare USA, Inc. All rights reserved.