Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility

Chen, Xi; Saxena, Vijay; Barr-Beare, Evan; Flemming, Weisi; Easterling, Robert S.; Becknell, Brian; Schwartz, George J.; Schwaderer, Andrew L.

doi:10.1152/ajprenal.00344.2014

Cited by 37 publications

(36 citation statements)

References 49 publications

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“…UPEC infection. Female IC and PC reporter mice were transurethrally inoculated with uropathogenic E. coli (UPEC strain CFT073) at a dose of 1 ϫ 10 8 colony forming units as described previously (13). One hour later, mice were killed, IC and PCs were flow sorted, and AMP mRNA was measured.…”

Section: Methodsmentioning

confidence: 99%

“…Collecting ducts consist of two cell types: principal cells (PCs) that express aquaporin 2 (AQP2) and regulate water along with salt reabsorption and intercalated cells (ICs) that express vacuolar H ϩ -ATPase (V-ATPase, B1 subunit) and help maintain acid-base homeostasis (4,14). Increasing evidence indicates that ICs also function as important innate immune cells notably, 1) bacteria preferentially attach to the apical surface of ICs (5); 2) ICs express innate immune proteins (10,25,29,31); 3) mice deficient in ICs are more susceptible to bacteruria and pyelonephritis (13,25); and 4) renal ICs sense and mediate inflammation (3). Studies of the innate immune role of ICs and/or collecting ducts have mostly been limited to a single gene or protein (24, 29 -31).…”

Section: Introductionmentioning

confidence: 99%

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Cell-specific qRT-PCR of renal epithelial cells reveals a novel innate immune signature in murine collecting duct

Saxena

Ketz

Chanley

et al. 2018

American Journal of Physiology-Renal Physiology

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The urinary tract is usually culture negative despite its close proximity to microbial flora. The precise mechanism by which the kidneys and urinary tract defends against infection is not well understood. The initial kidney cells to encounter ascending pathogens are the collecting tubule cells that consist of principal cells (PCs) that express aquaporin 2 (AQP2) and intercalated cells (ICs) that express vacuolar H-ATPase (V-ATPase, B1 subunit). We have previously shown that ICs are involved with the human renal innate immune defense. Here we generated two reporter mice, VATPase B1-cretdT mice to fluorescently label ICs and AQP2-cretdT mice to fluorescently label PCs, and then performed flow sorting to enrich PCs and ICs for analysis. Isolated ICs and PCs along with proximal tubular cells were used to measure antimicrobial peptide (AMP) mRNA expression. ICs and PCs were significantly enriched for AMPs. Isolated ICs responded to uropathogenic Escherichia coli (UPEC) challenge in vitro and had higher RNase4 gene expression than control while both ICs and PCs responded to UPEC challenge in vivo by upregulating Defb1 mRNA expression. To our knowledge, this is the first report of isolating murine collecting tubule cells and performing targeted analysis for multiple classes of AMPs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell-specific qRT-PCR of renal epithelial cells reveals a novel innate immune signature in murine collecting duct

Saxena

Ketz

Chanley

et al. 2018

American Journal of Physiology-Renal Physiology

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“…27 Similarly, in a model of experimental pyelonephritis, we have shown that mice lacking carbonic anhydrase 2 develop an increased renal UPEC burden and decreased UPEC clearance independent of serum bicarbonate concentrations or urine pH. 37 Carbonic anhydrase 2 is a key enzyme responsible for the generation of the hydrogen gradient of the intercalated cell. This finding therefore suggests that the innate immune activity of the intercalated cell requires intact acid-base control mechanisms.…”

Section: Introductionmentioning

confidence: 90%

“…This finding therefore suggests that the innate immune activity of the intercalated cell requires intact acid-base control mechanisms. 37 Although the mechanisms responsible for the antimicrobial activity of the collecting duct are only beginning to be described, intercalated cells have been shown to produce innate immune proteins such as IL-18, bacteriostatic proteins such as iron siderophores, and potent bactericidal AMPs (Table 1). 14,27,38 Some of these antimicrobial proteins are produced at high basal levels to prevent bacterial attachment whereas others are rapidly induced to facilitate pathogen clearance.…”

Section: Introductionmentioning

confidence: 99%

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

et al. 2015

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Urinary tract infections (UTIs), including pyelonephritis, are among the most common and serious infections encountered in nephrology practice. UTI risk is increased in selected patient populations with renal and urinary tract disorders. As the prevalence of antibiotic-resistant uropathogens increases, novel and alternative treatment options will be needed to reduce UTI-associated morbidity. Discoveries over the past decade demonstrate a fundamental role for the innate immune system in protecting the urothelium from bacterial challenge. Antimicrobial peptides, an integral component of this urothelial innate immune system, demonstrate potent bactericidal activity toward uropathogens and might represent a novel class of UTI therapeutics. The urothelium of the bladder and the renal epithelium secrete antimicrobial peptides into the urinary stream. In the kidney, intercalated cells--a cell-type involved in acid-base homeostasis--have been shown to be an important source of antimicrobial peptides. Intercalated cells have therefore become the focus of new investigations to explore their function during pyelonephritis and their role in maintaining urinary tract sterility. This Review provides an overview of UTI pathogenesis in the upper and lower urinary tract. We describe the role of intercalated cells and the innate immune response in preventing UTI, specifically highlighting the role of antimicrobial peptides in maintaining urinary tract sterility.

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“…For example, mice with intercalated celltargeted dysfunctions have increased risk of UTI with bacterial challenge. 75,76 Well-phenotyped cohorts of these conditions and genome-wide studies are needed to identify the entire milieu of the innate defense that may be targeted for novel therapeutics in preventing or treating UTIs.…”

Section: Resultsmentioning

confidence: 99%

The Genetics of Urinary Tract Infections and the Innate Defense of the Kidney and Urinary tract

2015

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The inheritance of APN morbidity was studied in threegeneration pedigrees of families.5 An increased frequency Keywords► innate immunity ► genetics ► urinary tract infections ► asymptomatic bacteriuria AbstractThe urinary tract is a sterile organ system. Urinary tract infections (UTIs) are common and often serious infections. Research has focused on uropathogen, environment, and host factors leading to UTI pathogenesis. A growing body of evidence exists implicating genetic factors that can contribute to UTI risks. In this review, we highlight genetic variations in aspects of the innate immune system critical to the host response to uropathogens. This overview includes genetic variations in pattern recognition receptor molecules, chemokines/cytokines, and neutrophil activation. We also comprehensively cover murine knockout models of UTI, genetic variations involved in renal scarring as a result of ascending UTIs, and asymptomatic bacteriuria.Ã Dr. Ambite and Dr. Rydstrom contributed equally to this work.

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Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility

Abstract: Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility.

Cited by 37 publications

References 49 publications

Cell-specific qRT-PCR of renal epithelial cells reveals a novel innate immune signature in murine collecting duct

Cell-specific qRT-PCR of renal epithelial cells reveals a novel innate immune signature in murine collecting duct

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

The Genetics of Urinary Tract Infections and the Innate Defense of the Kidney and Urinary tract

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