Increased expression of "muscle-specific" actin can be correlated with mesangial cell injury and proliferation in the rat. We performed similar immunohistochemical studies using two monoclonal antibodies (MoAb) to "muscle-specific" actins (HHF-35, a MoAb to pan muscle actin and alpha-SM-1, a MoAb to alpha-smooth muscle actin) on methyl Carnoy's fixed human renal biopsies which demonstrated a wide variety of inflammatory, proliferative, and non-proliferative glomerular diseases. Most glomerular diseases were associated with increased "smooth-muscle" actin expression. Exceptions almost invariably were disease settings without prominent cellular proliferation. As in the rat, there was a correlation of induced actin expression with increased glomerular cell proliferation, as detected by staining with a MoAb to proliferating cell nuclear antigen (PCNA). Double immunolabeling studies with an antibody to the leukocyte common antigen showed the great majority of PCNA+ proliferating cells to be intrinsic glomerular cells rather than infiltrating leukocytes. These studies demonstrate that phenotypic changes of mesangial cells occur in both human and experimental glomerulonephritis, and are identifiable in fixed tissue sections. These studies also suggest that markers of mesangial cell injury or activation and proliferation, such as immunostaining of renal biopsies for "muscle-specific" actins, might be useful diagnostic and/or prognostic indicators in proliferative or sclerosing glomerular diseases.