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  • Acidosis induces antimicrobial peptide expression and resistance to uropathogenic E. coli infection in kidney collecting duct cells via HIF-1α.

Acidosis induces antimicrobial peptide expression and resistance to uropathogenic E. coli infection in kidney collecting duct cells via HIF-1α.

American journal of physiology. Renal physiology (2019-12-17)
Hu Peng, Jeffrey M Purkerson, Robert S Freeman, Andrew L Schwaderer, George J Schwartz
ZUSAMMENFASSUNG

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.

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Sigma-Aldrich
5-(N-Ethyl-N-isopropyl)amilorid
Sigma-Aldrich
DMOG, ≥98% (HPLC)
Sigma-Aldrich
IOX2, ≥98% (HPLC)