Delineating signaling pathways and therapeutic approaches for stimulating kidney repair with obstructive uropathy

Abstract

Delineating signaling pathways and therapeutic approaches for stimulating kidney repair with obstructive uropathy. While a variety of congenital obstructive uropathies are encountered in patients, these conditions have a common pathological endpoint: renal injury and loss of kidney function. Obstructive uropathies remain the leading cause of pediatric renal insufficiency and renal failure, in large part, because the potential for permanent renal injury remains in many cases even following the surgical correction of pathologies of the urinary tract. Recently, both basic science and clinical studies have demonstrated that the kidney is capable of restoring renal structure and function following injury. However, little is known about the innate repair mechanisms of the kidney and how they become impaired following chronic obstruction. Importantly, our laboratory has found that the BMP-7 protein is required for several processes that contribute to the repair of obstruction-induced renal injuries, including the cessation of the TGF-²/fibrotic response to injury and the restoration of renal architecture. However, the potential for renal recovery following chronic obstruction is diminished due to the loss of BMP-7 expression and the subsequent dysregulation of kidney repair. Given that BMP-7 is also required for nephrogenesis, it is likely that the loss of BMP-7 expression in the obstructed kidney during the prenatal period also has significant, adverse effects on renal development and the long-term functional capacity of the kidney that are not yet understood. In further examining this critical event, we found that the loss of BMP-7 expression is mediated by histone deacetylase (HDAC) proteins that repress Bmp-7 transcription following chronic obstruction. Importantly, HDAC inhibition not only restores BMP-7 expression during chronic obstruction, but also stimulates the repair of obstruction-induced renal injuries that are otherwise irreversible. Since the loss of BMP-7 expression has been observed in patients with obstructive uropathies and other conditions that lead to chronic renal injury, it is imperative to develop a better understanding of this pivotal molecular event. Thus, we plan to further examine the regulation, long-term effects, and therapeutic importance of the loss of BMP-7 expression during chronic obstruction in the following specific aims: (1) To assess the role of individual HDAC isoforms in the suppression of BMP-7 expression following chronic obstruction. Despite the importance of BMP-7, little is known about its regulation. Accordingly, we will use a combination of pharmacologic and siRNA-based approaches to determine the role of individual HDAC isoforms in the suppression of BMP-7 expression. We will then extend these findings by using an inducible expression system in kidney cells to examine the effects of HDAC siRNA on BMP-7 activity in functional assays of BMP-7-dependent processes that contribute to injury repair. Finally, we will validate our results by determining the in vivo requirement for individual HDAC isoforms in the loss of BMP-7 expression and functional activity in a murine model of obstructive uropathy. (2) To evaluate novel therapeutic approaches for restoring BMP-7 activity, stimulating the innate repair mechanisms of the kidney, and ensuring proper renal development during the treatment of congenital obstructive uropathies. We will assess the ability of treatment with exogenous BMP-7 and pharmacologic, isoform-specific HDAC inhibitors that restore Bmp-7 expression for their ability to stimulate kidney repair and preserve renal function following obstruction at various stages of renal maturation, to prevent the obstruction-induced dysregulation of developmental processes, and to extend the nephrogenic capacity of renal progenitor cell populations in the developing kidney. (AU)