BMP7 dose-dependently stimulates proliferation and cadherin-11 expression via ERK and p38 in a murine metanephric mesenchymal cell line

BMP7 is expressed in ureteric buds and cap mesenchyme of the fetal kidney, mediating branching morphogenesis and survival and priming of metanephric mesenchyme. Although dose-dependent effects of BMP7 in collecting duct cells have been reported, studies in metanephric mesenchymal cells are lacking. We examined the effects of BMP7 on MAP kinase activation, proliferation, and expression of cadherins in a metanephric mesenchymal cell line MS7 by thymidine incorporation, immunoblot analysis, and quantitative real-time PCR. The levels of phosphorylated ERK (P-ERK) and phosphorylated p38 (P-p38) were not altered at 10 min, 1 h, and 6 h with low-dose BMP7 (0.25 nmol/L), but were increased at 24 h. At 24 h, P-ERK was increased with low-dose BMP7, but not by intermediate- (1 nmol/L) or high-dose (10 nmol/L) BMP7, whereas p38 was activated by intermediate-dose BMP7. Cell proliferation of MS7 was significantly increased by low- and intermediate-dose BMP7 and decreased by high-dose BMP7. A p38 inhibitor SB203580 5 μmol/L or a MEK inhibitor PD98059 5 μmol/L abolished BMP7-stimulated proliferation. Expression of cadherin-11, an adhesion molecule known to promote cell migration and compaction, was upregulated by intermediate-dose BMP7. BMP7-induced cadherin-11 expression was inhibited by cotreatment with SB203580 and PD98059. Finally, in metanephroi cultured with siRNA for cadherin-11, the number and thickness of cap mesenchyme were reduced. In conclusion, BMP7 exerts differential effects depending on the concentration; it may expand mesenchymal cells in the stroma where BMP7 concentration is low and may upregulate cadherin-11 promoting condensation around the tip of ureteric buds.