Ammonium chloride‐induced acidosis exacerbates cystitis and pyelonephritis caused by uropathogenic E. coli

Acute pyelonephritis caused by uropathogenic E. coli (UPEC) can cause renal scarring and lead to development of chronic kidney disease. Prevention of kidney injury requires an understanding of host factors and/or UPEC adaptive responses that are permissive for UPEC colonization of the urinary tract. Although some studies have suggested urine acidification limits UPEC growth in culture, other studies have described acid‐resistance mechanisms (AR) in E. coli such as the CadC/CadBA module that promotes adaptation to acid and nitrosative stress. Herein we confirm and extend our previous study by demonstrating that despite urine acidification, metabolic acidosis induced by dietary ammonium chloride (NH(4)Cl‐A) exacerbates cystitis and pyelonephritis in innate immune competent (C3H‐HeN) mice characterized by: (1) markedly elevated UPEC burden and increased chemokine/cytokine and NOS2 mRNA expression, (2) accumulation of intravesicular debris noninvasively detected by Power Doppler Ultrasound (PDUS), and (3) collecting duct (CD) dysfunction that manifests as a urine concentration defect. Bladder debris and CD dysfunction were due to the inflammatory response, as neither was observed in Tlr4‐deficient (C3H‐HeJ) mice. The effect of NH(4)Cl‐A was unrelated to acidosis as dietary administration of hydrochloric acid (HCl‐A) yielded a comparable acid–base status yet did not increase UPEC burden. NH(4)Cl‐A increased polyamines and decreased nitric oxide (NO) metabolites in urine indicating that excess dietary ammonium shifts arginine metabolism toward polyamines at the expense of NO synthesis. Furthermore, despite increased expression of NOS2, NO production post UPEC infection was attenuated in NH(4)Cl‐A mice compared to controls. Thus, in addition to induction of metabolic acidosis and urine acidification, excess dietary ammonium alters the polyamine:NO balance and thereby compromises NOS2‐mediated innate immune defense.