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Proper development and maintenance of urothelium is critical to its function. Uroplakins are expressed in developing and mature urothelium where they establish plaques associated with the permeability barrier. Their precise functional role in development and disease is unknown. Here, we disrupted Upk1b in vivo where its loss resulted in urothelial plaque disruption in the bladder and kidney. Upk1b RFP/RFP bladder urothelium appeared dysplastic with expansion of the progenitor cell markers, Krt14 and Krt5, increased Shh expression, and loss of terminal differentiation markers Krt20 and uroplakins. Upk1b RFP/RFP renal urothelium became stratified with altered cellular composition. Upk1b RFP/RFP mice developed age-dependent progressive hydronephrosis. Interestingly, 16% of Upk1b RFP/RFP mice possessed unilateral duplex kidneys. Our study expands the role of uroplakins, mechanistically links plaque formation to urinary tract development and function, and provides a tantalizing connection between congenital anomalies of the kidney and urinary tract along with functional deficits observed in a variety of urinary tract diseases. Thus, kidney and bladder urothelium are regionally distinct and remain highly plastic, capable of expansion through tissue-specific progenitor populations. Furthermore, Upk1b plays a previously unknown role in early kidney development representing a novel genetic target for congenital anomalies of the kidney and urinary tract.

Lack of major involvement of human uroplakin genes in vesicoureteral reflux: Implications for disease heterogeneity. background primary vesicoureteral reflux (vur) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. it affects about 1% of the young children and is thus one of the most common hereditary diseases. its associated nephropathy is an important cause of end-stage renal failure in children and adults. recent studies indicate that genetic ablation of mouse uroplakin (up) iii gene, which encodes a 47 kd urothelial-specific integral membrane protein forming urothelial plaques, causes vur and hydronephrosis. methods to begin to determine whether mutations in up genes might play a role in human vur, we genotyped all four up genes in 76 patients with radiologically proven primary vur by polymerase chain reaction (pcr) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. results eighteen single nucleotide polymorphisms (snps) were identified, seven of which were missense, with no truncation or frame shift mutations. since healthy relatives of the vur probands are not reliable negative controls for vur, we used a population of 90 race-matched, healthy individuals, unrelated to the vur patients, as controls to perform an association study. most of the snps were not found to be significantly associated with vur. however, snp1 of up ia gene affecting a c to t conversion and an ala7val change, and snp7 of up iii affecting a c to g conversion and a pro154ala change, were marginally associated with vur (both p = 0.08). studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of up iii snp7 in vur ( p = 0.036 adjusted for both subsets of cases vs. controls). conclusion such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.