The Impact of Methenamine Hippurate Treatment on Urothelial Integrity and Bladder Inflammation in Aged Female Mice and Women With Urinary Tract Infections

Sawhill, Jessica L; Mora, Amy; McDaniel, Kendall; Ligon, Marianne M.; Lowder, Jerry L.; Mysorekar, Indira U.; Chu, C. K.

doi:10.1097/spv.0000000000001185

Cited by 3 publications

(2 citation statements)

References 24 publications

(33 reference statements)

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“…The excessive shedding of urothelial cells captured in urines of aged female mice in the current study and noted previously in postmenopausal women (Meister et al, 2021) could be responsible in part for the dysregulated urothelial barrier function (Sawhill et al, 2022). The regenerative capacity of the urothelium in response to injury/infection/stress is notoriously robust (Murray et al, 2021; C. Wang et al, 2017; Wiessner et al, 2022).…”

Section: Discussionsupporting

confidence: 70%

“…For example, premature aging syndrome such as ataxia telangiectasia (AT), a severe neurodegenerative syndrome, is characterized by accumulation of γ-H2AX-enriched cytoplasmic DNA along with the expression of inflammatory genes, including IL-6 (Lan et al, 2019; Miller et al, 2021; Song et al, 2019). Previous work from our group has shown that the aged urothelium has increased permeability characterized by exposure of underlying urothelial cells and the stromal compartment to urinary content (Sawhill et al, 2022), which is highly detrimental to the normal urothelial function of maintaining an impermeable barrier to waste products and cytotoxic factors in urines (Dalghi et al, 2020). We posit that chronic exposure to urinary cytotoxic irritants could trigger DNA damage secondary to accumulation of ROS and drive CCF formation, leading to an SASP-associated inflammatory response coupled with age-associated dysfunctional lysosomal function and mitophagy defects.…”

Section: Discussionmentioning

confidence: 99%

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D-mannose ameliorates age-associated cellular senescence in the bladder urothelium and NLRP3/Gasdermin/IL-1β -driven pyroptotic epithelial cell shedding

Joshi

Salazar

Wang

et al. 2022

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Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combatting stress, and decreased regenerative capacity. Multiple diseases including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying how aging affects the urinary tract mucosa and the reason why aging correlates with disease are poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with decreased acid phosphatase activity and shows overall decreased autophagic flux. Aged bladders exhibit basally high accumulation of reactive oxygen species (ROS) and dampened redox response. Furthermore, the aged urothelium exhibits a canonical senescence-associated secretory phenotype (SASP) at baseline with continuous NLRP3-inflammasome- and Gasdermin D (GSDMD)-dependent pyroptotic cell death. Accordingly, we find that aged mice chronically exfoliate epithelial cells. When infected with uropathogenic E. coli, infected aged mice harbor more bacterial reservoirs post-infection and are prone to spontaneous recurrent UTI. Finally, treatment of aged mice with D-Mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses SASP, and limits pyroptotic epithelial shedding. Thus, normal aging dramatically affects bladder physiology with aging alone increasing baseline cellular stress and susceptibility to infection. Additionally, our results suggest that mannose supplementation could serve as a senotherapeutic to limit age-associated urothelial dysfunction.

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