Gene Expression and Cell Cycle Regulation in Obstructive Uropathy

Paul F. Austin, M.D.
Assistant Professor, Division of Urologic Surgery
Director of Pediatric Urology Research
Washington University School of Medicine

When the bladder outlet is obstructed, the bladder muscle undergoes hypertrophy as a compensatory response to the increased resistance to urinary outflow. If the obstruction becomes chronic, bladder wall compliance decreases due to excessive hypertrophy and fibrosis. The poor compliance may lead to vesicoureteral reflux, hydronephrosis and, ultimately, renal failure. The alteration of compliance is in part secondary to the hyperplastic response of the bladder smooth muscle cells (SMC) to increased bladder wall tension. Because of its clinical significance, I have begun to study the signal transduction pathways that mediate the stretch-induced bladder smooth muscle hyperplastic response.

To study the regulation of bladder SMC proliferation, we use an in vitro model of the bladder wall in which tension develops in bladder SMC growing in a three-dimensional collagen matrix and rodent models of bladder outlet obstruction to identify proteins that potentially mediate the smooth muscle hyperplastic response to bladder outlet obstruction. We also utilize genetically manipulated mice to confirm that these proteins have a role in the induction of hyperplasia in the bladder smooth muscle layer.

Using a model of the bladder wall in which bladder SMC are seeded in a collagen matrix and subject to varying degrees of resistance to contraction, we have found that the cell cycle control protein p27KIP1 is downregulated by the development of increased tension within the SMC. Similarly, p27KIP1 was found downregulated in vivo in a murine bladder wall with bladder outlet obstruction. Then, using genetically manipulated mice, we have found that the downregulation of p27KIP1 in response to stretch is necessary for bladder SMC hyperplasia during bladder outlet obstruction and that loss of p27KIP1 is sufficient to lower the threshold of the hyperplastic response of bladder SMC.

Cellular progression is controlled by many positive and negative regulators of the cell cycle. We will examine gene expression and cell cycle control in wild type and transgenic mice in the setting of bladder outlet obstruction. These studies could lead to better understanding of the mechanism(s) underlying obstructive uropathy and improved therapy.

FUNDING

1. NIH, NIDDK, K08 DK054864. 2003-2008. “Regulation of bladder smooth muscle hyperplasia.” Primary Investigator. ($602,531).

2. National Kidney Foundation. 2003-2006. “Combination therapy for refractory primary nocturnal enuresis.” Primary Investigator. ($15,000).

3. American College of Surgeons Faculty Research Fellowship. 2002-2004. “The regulation of bladder

smooth muscle proliferation in response to stretch.” Primary Investigator ($80,000).

4. Pfizer International Competitive Awards Program. 2002-2003. “Study of the signal transduction pathways through which doxazosin increases p27KIP1 levels in stretched bladder smooth muscle cells.” Primary Investigator. ($15,000).

Dr. Paul F. Austin's CV