Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

Abstract

Cadmium (Cd) is a heavy metal and environmental pollutant. The kidney is the principal target organ of Cd exposure. Previously, we found that low concentration of Cd damages the integrity of the glomerular filtration barrier. However, little is known about the effects of Cd on renal mesangial cells, which provide structural support for the glomerular capillary loops and regulate intraglomerular blood flow. In this study, human renal mesangial cells (HRMCs) were cultured in the presence of serum and treated with 4 μM Cd. We found that Cd activates the c-Jun N-terminal kinase (JNK) pathway, and increases the protein levels of c-Jun and c-Fos. Cd treatment also induces a decrease in proliferation and an increase in apoptosis of HRMCs, but only the decrease in HRMC proliferation was reversed by pretreatment with SP600125, an inhibitor of the JNK pathway. In addition, Cd does not change the expression of α-smooth muscle actin and platelet-derived growth factor receptor-β, the markers of mesangial cells, or the alignment of the filamentous actin (F-actin) cytoskeleton of HRMCs. Our data indicate that the JNK pathway mediates the inhibitory effects of Cd on HRMC proliferation.

Low-dose cadmium activates the JNK signaling pathway in human renal podocytes

“…At a concentration between 5 and 40 µM, Cd may induce apoptosis of BJAB cells by increasing DNA fragmentation and caspase-3 activity (33). In addition, at a concentration of 4 µM, Cd inhibits the proliferation of HRMCs via activation the JNK pathway (12). In the present study, treatment with 4 µM Cd increased phosphorylation of JNK, and c-Jun and c-Fos expression.…”

“…Depending on the experimental settings, Cd may differentially affect specific cell types in the glomerulus (12,26). As previously reported, although the vascular system is the primary target of Cd toxicity, a low concentration of Cd does not affect the proliferation and apoptosis of human umbilical vein endothelial cells or human renal glomerular endothelial cells (HRGeCs) (26)(27)(28).…”

“…As previously reported, although the vascular system is the primary target of Cd toxicity, a low concentration of Cd does not affect the proliferation and apoptosis of human umbilical vein endothelial cells or human renal glomerular endothelial cells (HRGeCs) (26)(27)(28). However, Cd may increase apoptosis of human renal mesangial cells (HRMCs) and decrease their proliferation (12). Podocytes are a terminally differentiated and highly specialized cell type in the glomerulus.…”

“…The three major MAPK pathways in mammalian cells are extracellular signal-regulated kinases, c-Jun N-terminal kinase (JNK) and p38 MAPK (11). JNK, also termed stress-activated protein kinase (SAPK), is activated by stress signals, including heat shock, ultraviolet light, osmotic stress and metabolic toxins (12)(13)(14). Activated JNK translocates to the nucleus and activates c-Jun and c-Fos, thus resulting in the formation of activating protein-1 (AP-1) (15).…”

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

“…The JNK pathway is activated by Cd in various cell types (7,46). Activation of JNK leads to the increase of c-Jun and c-Fos, which form the AP-1 complex that modulates target gene expression (47).…”