p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

Abstract

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 before 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 SB-203580, 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,

Induction of Hsp22 (HspB8) by estrogen and the metalloestrogen cadmium in estrogen receptor– positive breast cancer cells

“…Occasionally, cells that express readily detectable levels of Hsp27 are refractory to further induction of this sHSP by Cd, as has been shown for astroglia cells (Opanashuk and Finkelstein 1995). In a number of studies, Cd induced a robust and swift phosphorylation of Hsp27 in various cell types, including macrophages, renal podocytes, renal mesangial cells, and adrenal chromaffin cells (Radloff et al 1998;Eichler et al 2005;Hirano et al 2005;Leal et al 2007). In these cells, Cd is likely to activate signaling pathways that do not involve the ER.…”

“…With respect to Hsp27, this outcome was not expected because Cd robustly induced phosphorylation of this sHSP in a number of cell types (Radloff et al 1998;Eichler et al 2005;Hirano et al 2005;Leal et al 2007). In those studies, however, cells were exposed to Cd for shorter time periods (typically 0.5-2 hours) compared with the experiments shown in Figure 1A,B.…”

“…In many cells, Hsp27 is partially phosphorylated, including in MCF-7 cells (Ciocca et al 1992), and a variety of agents including Cd can increase the degree of its phosphorylation (Radloff et al 1998;Eichler et al 2005;Hirano et al 2005;Leal et al 2007). Hsp22 was also re-ported to be phosphorylated in vivo (Smith et al 2000).…”

Heat Shock Protein 27 Regulates Neutrophil Chemotaxis and Exocytosis through Two Independent Mechanisms

“…Monomeric nonphosphorylated Hsp27 binds to the barbed end of actin filaments in vitro, preventing the addition of globular actin (24,25). Phosphorylation of actin-associated Hsp27 results in its release from barbed ends, allowing actin polymerization to proceed (25,26), and phosphorylation of Hsp27 by the p38 MAPK pathway is required for actin reorganization (27)(28)(29)(30)(31)(32). In contrast, Zhu et al (33) reported that phosphorylation of Hsp27 induced its translocation from the cytosol to the actin cytoskeleton in platelets.…”

Phosphorylation of Hsp25 at serine 15 is promoted in immature fibers following <i>in situ</i> muscle contraction

“…Serine 15 and 86 (Ser15 and Ser86, respectively) are the major phosphorylation sites in Hsp25 [7][8][9] . Koh and Escobedo 10) reported that prolonged contraction caused immediate phosphorylation at both sites in Hsp25, as well as its translocation from the soluble to insoluble fraction in mouse extensor digitorum longus muscle.…”