Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

Significance of Renal Urothelium During Development and Disease

Jackson, Ashley R
http://orcid.org/0000-0002-1571-3906
http://rave.ohiolink.edu/etdc/view?acc_num=osu1459778047

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Congenital obstructive nephropathy is the most common cause of chronic kidney disease in children and represents a tremendous societal burden in terms of morbidity and mortality. Despite surgical intervention, more than half of the children with congenital obstructive nephropathy progress to end stage renal disease mandating a great need to develop an appropriate mouse model to directly assess the molecular pathways involved with disease pathogenesis. Our lab has identified a unique transgenic mouse line, designated mgb for megabladder that develops overt urinary tract obstruction in utero. Affected mice exhibit hydroureteronephrosis and progressive renal failure after birth providing an ideal model for the identification of molecular pathways involved in disease pathogenesis and the interrogation of diagnostic markers and therapeutic targets for children with congenital obstructive nephropathy. After developing a non-invasive technique to stratify disease progression by measuring hydronephrosis, we evaluated global renal transcriptomes in mgb mice. Most studies focus on the nephron, while our transcriptome analysis revealed an urothelial gene signature associated with worsening hydronephrosis. Although little is known about renal urothelium, its alterations during congenital obstructive nephropathy represent some of the earliest identified. Among the alterations, we identified an increase in urothelial proliferation, which correlated with an increase in expression of the progenitor cell marker Krt14. We found that the single cell layered renal urothelium adapted to obstruction by developing multilayered bladder-like characteristics. Schematically reconstructed proliferative regions revealed that some of the most dynamic were those juxtaposed to large neurovascular bundles. We found expanded and de novo expression of hallmark urothelial specialization markers, including a family of proteins with a largely unknown function in the kidney, uroplakins. From this, we hypothesized that modifications in the renal urothelium may transiently alter membrane permeability and cellular function. This relatively unknown tissue, and its unique cellular and molecular components may shed light on novel mechanisms for the activation of submucosal myofibroblasts during the initiation of fibrosis during chronic kidney disease. Finding collagen deposition just immediately underlying the renal urothelium basement membrane supports a role for this tissue in adaptation to congenital obstructive nephropathy. Very little is known about the renal urothelium. Expression of uroplakins in the renal urothelium is controversial, let alone the fact that we have little understanding of their function. Since pathogenesis during chronic kidney disease involves this tissue and these genes, we proposed to identify their roles within the normal urinary tract before targeting them in the context of obstruction. Insomuch, we identified the impact of Upk1b genetic ablation on urothelium using the Upk1bRFP/RFP mouse. After validating that the homozygous knock-in mutant did indeed lack Upk1b, we found that Upk1b was critical in urothelial plaque formation in vivo, as its absence caused aberrant expression of all other uroplakin family members resulting in plaque destabilization. Without the urothelial plaque, the urothelium was dysfunctional, and caused dramatic renal defects, allowing us identify novel structural and developmental roles for uroplakins and urothelium in the kidney. We concluded that Upk1b is critical in urothelial differentiation, plaque formation, progenitor regulation, homeostasis and structural integrity. We unexpectedly found a role for Upk1b during metanephric development since a subset of Upk1bRFP/RFP mice displayed renal collecting system duplication. In summary, our work indicates that the renal urothelium is capable of adapting to lower urinary tract obstruction through modifying key structural proteins. Proper urothelial differentiation is critical for normal development, function and pathogenesis of the urinary tract and the terminal differentiation gene Upk1b plays a key role in these processes. Further studies using the Mgb-/- and Upk1bRFP/RFP mice will provide unique working models to evaluate the complex etiology associated with chronic kidney disease.
Kirk McHugh, PhD (Advisor)
Daniel Birmingham, PhD (Committee Member)
Dawn Chandler, PhD (Committee Member)
Traci Wilgus, PhD (Committee Member)
268 p.
Biomedical Research
urothelium; renal urothelium; bladder; kidney; megabladder; congenital obstructive nephropathy; CON; chronic kidney disease; CKD; hydronephrosis; uroplakin; uroplakin 1b; upk1b; duplicated collecting system

Recommended Citations

Citations

  • Jackson, A. R. (2016). Significance of Renal Urothelium During Development and Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1459778047

    APA Style (7th edition)

  • Jackson, Ashley . Significance of Renal Urothelium During Development and Disease . 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1459778047.

    MLA Style (8th edition)

  • Jackson, Ashley . "Significance of Renal Urothelium During Development and Disease ." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1459778047

    Chicago Manual of Style (17th edition)

osu1459778047
428
© 2016, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.