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 part, because the potential fo permanent renal injury remains 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, the BMP-7 protein is required for several processes that contribute to the repair of obstruction-induced renal injuries, including the cessaion of the TGF-b/fibrotic response to injury and the restoration of renal architecture. Nonetheless, the potential for renal recovery following prolonged obstruction is diminished due to the HDAC-dependent suppression 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 los of BMP-7 expression in the obstructed kidney during the prenatal period also has significant, adverse effects on renal maturation and the long-term functional capacity of the kidney that are not yet understood. 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, this projec addresses the following specific aims:
(AIM 1) The molecular mechanisms that lead to the suppression of Bmp-7 transcription following chronic obstruction will be determined by using a combination of pharmacologic and siRNA-based approaches for isoform-specific HDAC inhibition to assess the role of individual HDAC proteins in the regulation of BMP-7 expression and its downstream functions that contribute to the repair of obstruction-induced renal injuries.
(AIM 2) The long-term effects of the loss of BMP-7 expression following chronic obstruction will be examined in the maturing kidney. An inducible Bmp-7 knockout mouse model will be used to mimic the obstruction- induced loss of BMP-7 expression and to determine its effects on renal maturation and the long-term functional capacity of the kidney.
(AIM 3) The therapeutic potential of approaches designed to restore BMP-7 function in the obstructed kidney will be evaluated by examining their ability to stimulate the innate repair mechanisms of the kidney, ensure proper renal development, and preserve kidney function in a mouse model of congenital obstructive uropathy. Together, these studies will lead to a better understanding of the innate repair mechanisms of the kidney along with novel, therapeutic approaches that may be used to optimize the regenerative potential of the developing kidney during the treatment of congenital obstructive uropathies.
Congenital obstructive uropathies are the leading cause of chronic kidney disease and kidney transplants in the pediatric population. While current surgical approaches are often able to correct these developmental abnormalities, the potential for permanent renal injury remains in many cases even after urinary tract function is successfully restored. This study aims to better understand how the innate repair mechanisms of the kidney become impaired following chronic obstruction with the long-term goal of developing novel, therapeutic approaches to optimize the regenerative potential of the kidney and preserve renal function during the treatment of patients with obstructive uropathies.
