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Acidosis induces antimicrobial peptide expression and resistance to uropathogenic
- Source :
- Am J Physiol Renal Physiol
- Publication Year :
- 2019
-
Abstract
- Acute pyelonephritis is frequently associated with metabolic acidosis. We previously reported that metabolic acidosis stimulates expression of hypoxia-inducible factor (HIF)-1α-induced target genes such as stromal derived factor-1 and cathelicidin, an antimicrobial peptide. Since the collecting duct (CD) plays a pivotal role in regulating acid-base homeostasis and is the first nephron segment encountered by an ascending microbial infection, we examined the contribution of HIF-1α to innate immune responses elicited by acid loading of an M-1 immortalized mouse CD cell line. Acid loading of confluent M-1 cells was achieved by culture in pH 6.8 medium supplemented with 5-(N-ethyl-N-isopropyl)-amiloride to block Na(+)/H(+) exchange activity for 24 h. Acid loading induced antimicrobial peptide [cathelicidin and β-defensin (Defb2 and Defb26)] mRNA expression and M-1 cell resistance to uropathogenic Escherichia coli infection to an extent similar to that obtained by inhibition of HIF prolyl hydroxylases, which promote HIF-1α protein degradation. The effect of acid loading on M-1 cell resistance to uropathogenic E. coli infection was reduced by inhibition of HIF-1α (PX-478), and, in combination with prolyl hydroxylase inhibitors, acidosis did not confer additional resistance. Thus, metabolic stress of acidosis triggers HIF-1α-dependent innate immune responses in CD (M-1) cells. Whether pharmacological stabilization of HIF prevents or ameliorates pyelonephritis in vivo warrants further investigation.
- Subjects :
- beta-Defensins
Protein Stability
Hypoxia-Inducible Factor 1, alpha Subunit
Immunity, Innate
Prolyl Hydroxylases
Cell Line
Up-Regulation
Mice
Cathelicidins
Host-Pathogen Interactions
Urinary Tract Infections
Animals
Uropathogenic Escherichia coli
Kidney Tubules, Collecting
Acidosis
Escherichia coli Infections
Antimicrobial Cationic Peptides
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 15221466
- Volume :
- 318
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Renal physiology
- Accession number :
- edsair.pmid..........6552b89e3732bf6198d782e95f748baa