Endogenous BMP-7 is a critical molecular determinant of the reversibility of obstruction-induced renal injuries

Abstract

Although obstructive uropathies are frequently correctable through surgery, the potential for permanent renal injury remains even following the successful correction of obstructions. Little is known about the intrinsic mechanisms that determine the reversibility of renal injuries. We and others found that exogenous bone morphogenic protein 7 (BMP-7) inhibits the pathogenesis of renal injury. Here, we examine the role of endogenous BMP-7 in the outcome of renal recovery following the correction of obstructive uropathies using a reversible murine model of ureteral obstruction. The role of BMP-7 was determined by examining the regulation of BMP-7 during renal recovery and by treating with either BMP-7-neutralizing antibodies or exogenous BMP-7. While BMP-7 is upregulated following the correction of obstructions that lead to reversible renal injury, the upregulation of BMP-7 is diminished following the correction of prolonged obstructions that lead to irreversible renal injury. The activation of the BMP-7 pathway is required for several processes that contribute to renal recovery including the suppression of transforming growth factor-β-dependent profibrotic pathways, the restoration of renal architecture, and the resolution of fibrotic changes in the kidney. Importantly, the therapeutic restoration of BMP-7 enhances renal recovery following the correction of prolonged obstructions that typically lead to irreversible renal injury. Together, these findings show that, while BMP-7 plays a critical role in the repair of obstruction-induced renal injuries, the potential for renal recovery from prolonged obstruction is diminished, in part, due to the dysregulation of BMP-7. Accordingly, renal recovery from obstructive uropathies may be optimized through timely intervention and adjuvant approaches to restore BMP-7 activity.