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Abstract
Objective: Recent studies have implicated an enhanced secretion of IL1β through activation of the Nod-like receptor family, pyrin domain containing 3 (Nlrp3)-inflammasome as the pro-inflammatory signal in animal models of the gout, chronic kidney disease (CKD), atherosclerosis, metabolic syndrome, type 2 diabetes mellitus, but its contribution to hypertension is not established. We aimed to demonstrate the role of the Nlrp3-inflammasome in the two-kidneys, one clip (2K1C) Goldblatt model of hypertension in Nlrp3-/- and apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc)-/- and wild type control male mice. Study design: 2K1C hypertension was generated by narrowing left renal artery using U-shaped stainless steel clip. BP and heart rate were recorded intra-arterially with a computerized data-acquisition system in conscious mice. Plasma renin activity and concentration were measured by radioimmunoassay. Renal transcript levels of Nlrp3, Asc, Casp1, IL1A, IL1β, and IL6 were assessed by RT-Q-PCR. Results: Results show that Nlrp3-/- and Asc-/- mice are protected from developing hypertension and have lower circulating levels of plasma renin and serum amyloid A (SAA) and IL6, in comparison to wild type (WT) control mice. RNA levels of SAA, Nlrp3, and IL1β are increased in the ischemic kidney of the WT control mice. Administration of anti-IL1β antibody to the WT control mice attenuated the increase of blood pressure and renin in the 2K1C model. The results suggest that NALP3 inflammasome has an impact on blood pressure and renin secretion during renal hypoperfusion induced by renal arterial clip and contributes to renin-dependent renovascular hypertension. Conclusion: These findings show that Nlrp3-inflammasome mediated production of IL1 is linked to the development of renovascular hypertension and might be a novel target for the treatment of renovascular hypertension, CKD and other inflammatory diseases with hypertension.
Highlights
Hypertension affects approximately 25% of the adult population worldwide, and its prevalence is predicted to increase by 60% by 2025, when a total of 1.56 billion people may be affected [1]
Results show that Nlrp3-/- and a caspase recruitment domain (Asc)-/- mice are protected from developing hypertension and have lower circulating levels of plasma renin and serum amyloid A (SAA) and IL6, in comparison to wild type (WT) control mice
The results suggest that NALP3 inflammasome has an impact on blood pressure and renin secretion during renal hypoperfusion induced by renal arterial clip and contributes to renin-dependent renovascular hypertension
Summary
To assess the role of Nlrp3-inflammasome in the development of renin-dependent hypertension, Nlrp3-/- and Asc-/- mice and wild type (WT) control mice were applied in 2K1C model of hypertension. (Figure 1A, 1B, 1C) shows that in WT mice, mean blood pressure, PRA, and kidney weight to body weight index (KWI) are significantly increased at week 12 after renal artery clamping. PRA and PRC were not raised by the 2K1C procedure in Nlrp3-/- and Asc-/- mice clamping of the renal artery lead to a comparable renal ischemia and reduction of kidney weight on the clipped kidney in all three groups of mice indicating that the renal arterial clamping had a comparable effect on renal blood perfusion among 2K1C treated animals (Figure 1C and Table 1). The mean level in sham-operated mice (n=7) was 94ng/ml of total IL1β, compared to a mean value of 85ng/ml in 2K1C kidneys (n=6, p>0.05) These results indicate that there was no overall change in total IL1β levels, but do not exclude an increase in active p17. These results indicate that renal ischemia induced pro-inflammatory gene transcription including RNA for Nlrp, IL1b and IL1a, and was associated with the development of hyperreninemia and hypertension. The treatment prevented the rise of PRA and BP in 2K1C mice and had no effect on PRA and BP in sham animals, suggesting that IL1β secretion may participate in the regulation of renin secretion and the development of hypertension, and explains why Nlrp3-/- and Asc-/- mice did not develop hypertension in the 2K1C model
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