Simoni Aaron, Bochter M Skye, Linn-Peirano Sarah, Salamon Kristin, Becknell Brian, Cortado Hanna, Jackson Ashley R, Schwartz Laura, Spencer John David
Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH, USA.
College of Veterinary Medicine, University of Tennessee Institute of Agriculture, Knoxville, TN, USA.
Life Sci Alliance. 2025 Jul 23;8(10). doi: 10.26508/lsa.202503292. Print 2025 Oct.
Despite advancements in our understanding of urinary tract infection (UTI) pathogenesis, UTIs remain a leading cause of morbidity, partly because of an incomplete understanding of the molecular pathways governing bladder antibacterial defenses. Here, we demonstrate that phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, is a critical modulator of bladder urothelial immune defenses and vulnerability to UTIs caused by uropathogenic (UPEC). PTEN silencing in human bladder urothelial cells increases susceptibility to UPEC in vitro, and urothelial-specific PTEN knockout mice exhibit increased bacterial titers in the urine, bladder, and kidneys after in vivo transurethral UPEC infection. Mechanistically, PTEN deficiency enhances Akt phosphorylation, amplifying NFκB and FAK activity. Silencing NFκB or FAK in PTEN-deficient cells restores resistance to UPEC. These findings establish PTEN as an important regulator of bladder urothelial defenses, balancing immune activation and urothelial structural integrity to protect against UTI.
尽管我们对尿路感染（UTI）发病机制的理解有所进步，但UTI仍是发病的主要原因，部分原因是对调控膀胱抗菌防御的分子途径了解不全面。在此，我们证明磷酸酶和张力蛋白同源物（PTEN），一种PI3K/Akt信号通路的负调节因子，是膀胱尿路上皮免疫防御以及对尿路致病性大肠杆菌（UPEC）引起的UTI易感性的关键调节因子。人膀胱尿路上皮细胞中的PTEN沉默会增加体外对UPEC的易感性，并且尿路上皮特异性PTEN基因敲除小鼠在体内经尿道感染UPEC后，尿液、膀胱和肾脏中的细菌滴度会增加。从机制上讲，PTEN缺乏会增强Akt磷酸化，放大NFκB和FAK活性。在PTEN缺陷细胞中沉默NFκB或FAK可恢复对UPEC的抗性。这些发现确立了PTEN作为膀胱尿路上皮防御的重要调节因子，平衡免疫激活和尿路上皮结构完整性以预防UTI。
