The Homeodomain Transcription Factor NKX3.1 Modulates Bladder Outlet Obstruction Induced Fibrosis in Mice

Abstract

Fibrosis is an irreversible remodeling process characterized by the deposition of collagen in the extracellular matrix of various organs through a variety of pathologies in children, leading to the stiffening of healthy tissues and organ dysfunction. Despite the prevalence of fibrotic disease in children, large gaps exist in our understanding of the mechanisms that lead to fibrosis, and there are currently no therapies to treat or reverse it. We previously observed that castration significantly reduces fibrosis in the bladders of male mice that have been partially obstructed. Here, we investigated if the expression of androgen response genes were altered in mouse bladders after partial bladder outlet obstruction (PO). Using a QPCR microarray and QRTPCR we found that PO was sufficient to increase expression of the androgen response gene Nkx3.1. Consistent with this was an increase in the expression of NKX3.1 protein. Immunofluorescent antibody localization demonstrated nuclear NKX3.1 in most bladder cells after PO. We tested if genetic deletion of Nkx3.1 alters remodeling of the bladder wall after PO. After PO, Nkx3.1KO/KO bladders underwent remodeling, demonstrating smaller bladder area, thickness, and bladder: body weight ratios than obstructed, wild type controls. Remarkably, Nkx3.1KO/KO specifically affected histological parameters of fibrosis, including reduced collagen to muscle ratio. Loss of Nkx3.1 altered collagen and smooth muscle cytoskeletal gene expression following PO which supported our histologic findings. Together these findings indicated that after PO, Nkx3.1 expression is induced in the bladder and that it mediates important pathways that lead to tissue fibrosis. As Nkx3.1 is an androgen response gene, our data suggest a possible mechanism by which fibrosis is mediated in male mice and opens the possibility of a molecular pathway mediated by NKX3.1 that could explain sexual dimorphism in bladder fibrosis.

Single-cell transcriptome reveals cellular heterogeneity and lineage-specific regulatory changes of fibroblasts in post-traumatic urethral stricture

“…LHX9 interacts with p53 to inhibit the expression of glycolytic enzyme PGK1 and regulate cell proliferation [ 21 ]. Nkx3.1 is an important mediator of bladder fibrosis in bladder outlet obstruction and is responsible for activating the pathway leading to tissue fibrosis [ 22 ]. NR2F1 can regulate the cell cycle dynamics of neocortical progenitor cells and affect the balance between the proliferation and differentiation of neural progenitor cells [ 23 ].…”

Dietary Risk Factors for Pediatric Kidney Stones: A Case-Control Study

“…From the completed surveys, we derived energy and nutrient intakes per standard procedures developed by the HSPH Nutrition Department. 14 Similar studies using the same procedures were published previously. 15 Briefly, energy and basic nutrient composition values were assigned for each item and the intake frequency in the dietary survey.…”

The Role of Nkx3.1 in Cancers and Stemness

“…Nkx3.1 is an important mediator of bladder fibrosis in bladder outlet obstruction (75). Fibrosis leads to stiffening of healthy tissues and organ dysfunction due to the irreversible remodelling caused by deposition of collagen in the extracellular matrix of various organs.…”

“…Fibrosis leads to stiffening of healthy tissues and organ dysfunction due to the irreversible remodelling caused by deposition of collagen in the extracellular matrix of various organs. Expression of Nkx3.1 is induced in the bladder following partial bladder outlet obstruction (PO), and is responsible for activation of pathways leading to tissue fibrosis (75). Even though the bladder appears to be functionally and morphologically intact, fibrosis is attenuated in the absence of Nkx3.1 (75).…”

“…Expression of Nkx3.1 is induced in the bladder following partial bladder outlet obstruction (PO), and is responsible for activation of pathways leading to tissue fibrosis (75). Even though the bladder appears to be functionally and morphologically intact, fibrosis is attenuated in the absence of Nkx3.1 (75). Nkx3.1 is also a potential therapeutic target for the treatment of nasopharyngeal carcinoma (NPC), along with cyclin B2 (CCNB2) (76).…”