title: Inhibition of NF-kappaB ameliorates sepsis-induced downregulation of aquaporin-2/V2 receptor expression and acute renal failure in vivo.
abstract: Acute renal failure (ARF) is frequently associated with polyuria and urine concentration defects and it is a severe complication of sepsis because it increases the mortality rate. Inhibition of NF-kappaB activation has been suggested to provide a useful strategy for the treatment of septic shock. However, the impact on sepsis-induced ARF is still unclear. Therefore, we examined the effect of pyrrolidine dithiocarbamate (PDTC) and of small interfering RNA (siRNA) silencing NF-kappaB p50/p105 on sepsis-induced downregulation of vasopressin V(2) receptors and aquaporin (AQP)-2 channels using a cecal ligation and puncture (CLP) mouse model. CLP caused a time-dependent downregulation of renal vasopressin V(2) receptor and of AQP2 expression without alterations in plasma vasopressin levels. Renal activation of NF-kappaB in response to CLP was attenuated by PDTC pretreatment, which also attenuated the downregulation of V(2) receptor and AQP2 expression. Furthermore, a strong nuclear staining for the NF-kappaB p50 subunit throughout the whole kidney in response to CLP was observed. siRNA against NF-kappaB p50 attenuated the CLP-induced nuclear translocation of the p50 subunit and the CLP-induced downregulation of V(2) receptor and AQP2 expression. Additionally, PDTC and siRNA pretreatment inhibited the CLP-induced increase in renal TNF-alpha and IL-1beta concentration and NOS-2 mRNA abundance. Moreover, PDTC and siRNA pretreatment ameliorated CLP-induced hypotension and ARF. Our findings suggest that NF-kappaB activation is of importance for the downregulation of AQP2 channel and vasopressin V(2) receptor expression during sepsis. In addition, our data indicate that NF-kappaB inhibition ameliorates sepsis-induced ARF.
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstr. 31, D-93040 Regensburg, Germany. klaus.hoecherl@chemie.uni-regensburg.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Höcherl
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmidt
authors.forename: Birgül
authors.initials: B
authors.lastname: Kurt
authors.forename: Michael
authors.initials: M
authors.lastname: Bucher
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D051399:Aquaporin 2 / Q000378:metabolism*; D002432:Cecum / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D017483:Receptors, Vasopressin / Q000378:metabolism*; D018805:Sepsis / Q000150:complications* / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014667:Vasopressins / Q000097:blood
chemical_list: D000975:Antioxidants; D051399:Aquaporin 2; D053583:Interleukin-1beta; D016328:NF-kappa B; D011759:Pyrrolidines; D017483:Receptors, Vasopressin; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D014667:Vasopressins; C020972:pyrrolidine dithiocarbamic acid