Pathophysiology of Renal Disease and ProgressionActivation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human GlomerulopathiesMasaki, Takao*; Stambe, Cosimo*,†; Hill, Prudence A.§; Dowling, John‡; Atkins, Robert C.*,†; Nikolic-Paterson, David J.*,† Author Information *Department of Nephrology, †Monash University Department of Medicine, and ‡Department of Pathology, Monash Medical Centre, Clayton, Victoria, Australia; and §Department of Anatomical Pathology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia. Correspondence to Dr. David J. Nikolic-Paterson, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: 61-3-9594 3535; Fax: 61-3-9594-6530; E-mail: [email protected] Accepted April 20, 2004 Received January 05, 2004 Journal of the American Society of Nephrology 15(7):p 1835-1843, July 2004. | DOI: 10.1097/01.ASN.0000130623.66271.67 Buy Metrics Abstract ABSTRACT. Examined was extracellular-signal regulated kinase (ERK) activation in normal human kidney (n = 2) and a cohort of glomerulopathies by immunohistochemistry staining for the dual-phosphorylated form of ERK (p-ERK). Cell proliferation was determined by expression of the proliferating cell nuclear antigen (PCNA). In normal human kidney, p-ERK was largely restricted to the cytoplasm of cells of the collecting duct (CD). In glomerulopathies, glomerular ERK activation was highly variable. However, there was colocalization of cell proliferation and ERK activation in the glomerular tuft and crescents. Tubular ERK activation in the different glomerulopathies was confined to the CD in areas with normal architecture. In contrast, ERK activation was prominent in tubules and interstitial cells in areas of tubulointerstitial damage. ERK activation was observed in glomerular and interstitial α-smooth muscle actin–positive myofibroblasts, but few macrophages or T cells showed ERK activation. There was a significant correlation between glomerular p-ERK+ and PCNA+ cells and between tubular p-ERK+ and PCNA+ cells. Glomerular p-ERK+ cells correlated with glomerular cellularity and the percentage of glomeruli with segmental lesions. Tubular p-ERK+ cells correlated with renal dysfunction and interstitial fibrosis and tubular atrophy. In conclusion, activation of the ERK pathway in human glomerulopathies correlates with cell proliferation, histologic lesions, and renal dysfunction. ERK activation may promote renal repair through tubular proliferation while promoting renal fibrosis via proliferation of glomerular and interstitial myofibroblasts. Copyright © 2004 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.