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: Klaus Höcherl, Christoph Schmidt, Birgül Kurt, Michael Bucher
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 298 Issue 1 Pg. F196-204 (Jan 2010) ISSN: 1522-1466 [Electronic] United States
• PMID: 19828675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Aquaporin 2
• Interleukin-1beta
• NF-kappa B
• Pyrrolidines
• Receptors, Vasopressin
• Thiocarbamates
• Tumor Necrosis Factor-alpha
• Vasopressins
• pyrrolidine dithiocarbamic acid

Topics

• Acute Kidney Injury (etiology, metabolism, prevention & control)
• Animals
• Antioxidants (pharmacology)
• Aquaporin 2 (metabolism)
• Cecum (physiopathology)
• Disease Models, Animal
• Down-Regulation (drug effects, physiology)
• Interleukin-1beta (metabolism)
• Ligation
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors, metabolism)
• Pyrrolidines (pharmacology)
• Receptors, Vasopressin (metabolism)
• Sepsis (complications, metabolism)
• Thiocarbamates (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• Vasopressins (blood)