Submitted on June 7, 2004
Accepted on January 25, 2005
p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli
Sahoko Hirano1, Xiankui Sun1, Cheryl A. DeGuzman2, Richard F. Ransom3, Kenneth R. McLeish4, William E. Smoyer3, Eric A. Shelden1, Michael J. Welsh1, and Rainer Benndorf1*
1 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
2 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Toxicology Program, Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
3 Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA
4 Molecular Signaling Group, Kidney Disease Program, University of Louisville, Louisville, Kentucky, USA
* To whom correspondence should be addressed. E-mail: rbenndo{at}umich.edu.
The environmental pollutant cadmium affects human health with the kidney being a primary
target. In addition to proximal tubules, glomeruli and their contractile mesangial cells have
also been identified as targets of cadmium nephrotoxicity. Glomerular contraction is thought
to contribute to reduced glomerular filtration, a characteristic of cadmium nephrotoxicity.
Because p38 MAPK/HSP25 signaling has been implicated in smooth muscle contraction, we
examined its role in cadmium-induced contraction of mesangial cells. We report that exposure
of mesangial cells to cadmium resulted in 1) cell contraction, 2) activation of MAP kinases, 3)
increased HSP25 phosphorylation coincident with p38 MAP kinase activation, 4) sequential
phosphorylation of the two phosphorylation sites of mouse HSP25 with Ser15 being
phosphorylated prior to Ser86, 5) reduction of oligomeric size of HSP25, and 6) association of
HSP25 with microfilaments. Exposure of isolated rat glomeruli to cadmium also resulted in
contraction and increased HSP25 phosphorylation. The cadmium-induced responses were
inhibited by the specific p38 MAP kinase inhibitor SB203580, and cadmium-induced
phosphorylation of HSP25 was inhibited by expression of a dominant-negative p38 MAP
kinase mutant. These findings tentatively suggest that cadmium-induced nephrotoxicity results
in part from glomerular contraction due to p38 MAP kinase/HSP25 signaling-dependent
contraction of mesangial cells. With regard to the cellular action of HSP25, these data support
a change in paradigm: In addition to its well-established cytoprotective function, HSP25 may
also be involved in processes which ultimately lead to adverse effects, as is observed in the
response of mesangial cells to cadmium.
