Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

Abstract

Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb −/−) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb −/− kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb −/− kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngalhigh versus Ngallow kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb −/− mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction.

Uroplakin 1b is critical in urinary tract development and urothelial differentiation and homeostasis

“…7, 8, 24, 25 These observations are also supported by studies in our lab where urothelial remodeling in hydronephrotic kidneys involved increased urothelial proliferation in Krt14-expressing cells, urothelial stratification, and de novo Upk expression. 6 …”

“…6, 37, 38 Primary antibodies: Upk1a, Upk2, Upk3b, Shh, p63 (Santa Cruz Biotechnology, Santa Cruz, CA), Upk3a (Fitzgerald Industries International, Acton, MA), Krt13, Krt5, Krt14 (Covance, Princeton, NJ), and Krt20 (Dako North America, Inc., Carpinteria, CA) were detected using Anti-Polyvalent or Anti-Goat and, HRP/DAB reagents (Scytek Laboratories, Logan, UT). Sections were imaged using an Olympus BX51 microscope and CX9000 camera.…”

“…6 12.5ng of cDNA and gene-specific primers/probes were used (Roche NimbleGen, Incorporated, Madison, WI). Triplicate reactions included Gapdh .…”

“…4, 5 Furthermore, studies in our lab and others have shown molecular and structural alterations in renal urothelium to be an early response to tissue injury. 6-8 …”

Role of renal urothelium in the development and progression of kidney disease

“…Studies from our lab and others have shown that urothelial remodeling is an early response to a variety of urinary tract pathologies including congenital obstructive nephropathy, ischemia, unilateral ureteral obstruction and infection [26–30]. Six of the top ten most differentially expressed genes in severely hydronephrotic mgb −/− kidneys were found in the renal urothelium, with four of the top five including the four major uroplakins - Upk1a , Upk1b , Upk2 and Upk3a [26].…”