Vesico-ureteric reflux: using mouse models to understand a common congenital urinary tract defect

Murawski, Inga J.; Watt, Christine L.; Gupta, Indra R.

doi:10.1007/s00467-011-1821-1

Cited by 19 publications

(15 citation statements)

References 110 publications

(117 reference statements)

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“…Since there was little evidence of colonization of the C57BL/6 kidney with UPECs in our model of UTI, we turned to another model of urinary infection: pyelonephritis in the C3H/HeN mouse. These mice are susceptible to UPEC-mediated pyelonephritis because they are naturally prone to vesiculoureteral reflux due to the Vurm1 locus (83,84). We confirmed the reflux using bioluminescent CFT073 UPEC-lux, which rapidly ascended to the kidney ( Figure 4, E and F).…”

Section: Figuresupporting

confidence: 56%

α–Intercalated cells defend the urinary system from bacterial infection

Paragas¹,

Kulkarni²,

Werth³

et al. 2014

J. Clin. Invest.

129

111

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α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2. The presence of LCN2 in urine was both necessary and sufficient to control the urinary tract infection through iron sequestration, even in the harsh condition of urine acidification. In mice lacking A-ICs, both urinary LCN2 and urinary acidification were reduced, and consequently bacterial clearance was limited. Together these results indicate that A-ICs, which are known to regulate acid-base metabolism, are also critical for urinary defense against pathogenic bacteria. They respond to both cystitis and pyelonephritis by delivering bacteriostatic chemical agents to the lower urinary system.

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Section: Figuresupporting

confidence: 56%

α–Intercalated cells defend the urinary system from bacterial infection

Paragas¹,

Kulkarni²,

Werth³

et al. 2014

J. Clin. Invest.

129

111

View full text Add to dashboard Cite

show abstract

“…In a newly developed mouse model of rUTI, the C3H mouse strain – known to have increased vesicoureteral reflux compared to C57BL/6 mice [108] – can be sensitized to later infection. Following an initial infection (experimentally resolved by treatment with antibiotics) and upon subsequent re-challenge with a later infection, these “sensitized” mice were more likely than naïve mice to suffer persistent bacteriuria and chronic cystitis [62].…”

Section: Emerging Clinically Relevant Models For Utimentioning

confidence: 99%

Urinary Tract Infection: Pathogenesis and Outlook

McLellan

Hunstad

2016

Trends in Molecular Medicine

265

206

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The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities.

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“…4,5 Recent murine distal ureter genetic and developmental modeling studies implicated a significant contribution of disordered bladder trigone and common nephric duct interactions in PVUR development. [6][7][8][9][10][11][12][13] Although these theories provide explanations for early events during embryogenesis that are likely to give rise to renal dysplasia and VUR, they do not completely explain the pathogenesis of PVUR. VUR is highly heritable, and although many loci have been found, the specific genes encoded by these loci have remained elusive.…”

mentioning

confidence: 99%

TNXB Mutations Can Cause Vesicoureteral Reflux

Gbadegesin

Brophy

Adeyemo

et al. 2013

Journal of the American Society of Nephrology

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Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.

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Vesico-ureteric reflux: using mouse models to understand a common congenital urinary tract defect

Cited by 19 publications

References 110 publications

α–Intercalated cells defend the urinary system from bacterial infection

α–Intercalated cells defend the urinary system from bacterial infection

Urinary Tract Infection: Pathogenesis and Outlook

TNXB Mutations Can Cause Vesicoureteral Reflux

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