Inhibition of IL-1β by Aliskiren Improved Renal AQP2 Expression and Urinary Concentration Defect in Ureteral Obstruction and Release

Abstract

We previously demonstrated that ureteral obstruction is associated with a urinary concentrating defect and reduced expression of renal aquaporins (AQPs), in which the renin–angiotensin system (RAS) may play an important role. The aims of the present study were to examine whether the renin inhibitor aliskiren could prevent the reduction in AQP expression and improve the urinary concentrating capacity in mice with bilateral ureteral obstruction (BUO) and BUO release. BUO was performed for 24 h, and BUO release was performed for 1 (B-R1D) or 3 days (B-R3D) with or without aliskiren treatment. Aliskiren prevented polyuria and decreased urine osmolality induced by B-R3D. In mice with BUO and BUO release, aliskiren attenuated the reduction in AQP2 protein and mRNA expression in the obstructed kidneys. B-R3D increased the protein expression of NLRP3 inflammasome components ASC, caspase-1, and interleukin-1β in the obstructed kidneys, which was markedly prevented by aliskiren. Moreover, the NF-κB inhibitor Bay 11-7082 blocked NLRP3 inflammasome activation and attenuated the decrease in AQP2 protein expression in primary cultured rat inner medullary collecting duct cells treated with angiotensin II. These results indicate that the renin inhibitor aliskiren increases water channel AQP2 expression at least partially by suppressing NLRP3 inflammasome activation in the obstructed kidneys of mice with BUO and BUO release.

Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney

“…Our recent studies 36 , 37 have revealed an inhibitory role of NLRP3 inflammasome in the regulation of aquaporins in the kidneys. In order to unravel the potential mechanism by which cholesterol may affect the protein expression of AQP2, the protein expression profiles of ASC, an adaptor of NLRP3 inflammasome, were examined in the kidney specimens of patients with or without atorvastatin treatment.…”

“…Next we examined a potential mechanism by which cholesterol may impact the protein expression of AQP2. Our recent studies 36 , 37 have revealed an inhibitory role of NLRP3 inflammasome in the regulation of aquaporins of the kidneys. As expected, the protein expression of ASC monomer, cleaved Caspase-1 (p20) and cleaved IL-1β in the kidneys was found to be upregulated in wild type mice on a HFD; while in nlrp3 -/- mice, the HFD seemed to have failed to induce significant changes in the protein expression of ASC, Caspase-1 (p20) and cleaved IL-1β expression (Figure 3 A and B).…”

“…Particularly, the protein expression of adaptor ASC monomer that is critical for maturation of IL-1β was found to be increased. Our previous studies have demonstrated that IL-1β can decrease gene and protein expression of AQP2 in the principal cells of collecting ducts 35 - 37 .…”

“…Local factors in the kidneys, including pro-inflammatory cytokines (e.g. IL-1β) have also been shown to affect the protein expression of aquaporins in several kidney injury models 35 - 37 . Although an earlier study has demonstrated downregulated levels of sodium transporters and aquaporins in the tubular segments and collecting ducts of diabetic Zucker rats, the underlying molecular mechanism remains elusive 38 .…”

GSK‐3β inhibitor TDZD‐8 prevents reduction of aquaporin‐1 expression via activating autophagy under renal ischemia reperfusion injury

“…Immunofluorescence staining was performed as described previously. 31 After dewaxing and rehydration, kidney tissue For inner medullary collecting duct 3 (IMCD3) cells, in brief, filters were detached from the holders, and cells were fixed with methanol for 2 minutes at −20℃, and permeabilized with PBS-Triton 0.3% for 25 minutes at room temperature and then vacuum permeabilization buffer. Filters were incubated with the rabbit polyclonal anti-p62 (1:200), anti-LC3B (1:200, 18725-1-AP, Proteintech) and anti-LAMP1 (1:200) antibody or mouse monoclonal anti-ASC (1:50, sc-514414, Santa Cruz Biotechnology) overnight at 4℃.…”