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Characteristics and Hypertensive Actions of Renal Medullary NALP3 Inflammasomes in Mice
Author(s) -
Xia Min,
Xiong Jing,
Boini Krishna,
Abais Justine,
Li Pin-Lan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.879.4
Subject(s) - nalp3 , kidney , endocrinology , medicine , renal medulla , inflammasome , blood pressure , chemistry , medulla , renovascular hypertension , renal function , inflammation
Recent studies have indicated that local inflammation is importantly involved in the regulation of renal function and arterial blood pressure. However, it remains unknown how such local inflammation is triggered intracellularly in the kidney. The present study was designed to characterize the expression and function of NALP3 inflammasome in the kidney and also test its role in renal medulla of arterial blood pressure regulation. IHC analysis showed that NALP3, ASC and caspase‐1 were universally distributed in the kidney. Biochemical analysis showed that caspase‐1 activity and IL‐1β production was 2 fold higher in the renal medulla than in cortex. For renal nephron segment analysis, confocal microscopy and RT‐PCR analysis revealed that NALP3, ASC and caspase‐1 were enriched in thick ascending limb of Henle. In chronic animal experiments, medullary interstitial infusion of ATP (1 mM/100 g bw./hr) significantly increased the salt sensitivity of arterial blood pressure (from 100±2 to 123±2 mmHg). Pretreatment of mice with WEHD, an caspase‐1 inhibitor (0.1 mg/100 g bw./d) blocked the ATP‐induced hypertension (100 ±4 mmHg). The sodium balance studies showed that ATP increased sodium retention by 69%, but not in WEHD group. Confocal microscopy showed that increased colocalization of NALP3 with ASC or caspase‐1 in ATP infused mice compared to control mice fed a high salt diet. Consistently, caspase‐1 activity (1.4 fold) and IL‐1β production (1.4 fold) increased in the renal medulla in ATP‐infused mice versus vehicle‐infused mice. IHC analysis of CD43 (a T‐cell marker) showed that T‐cells were accumulated more in the ATP‐infused renal medulla. In conclusion, the NALP3 inflammasome molecules are most abundant in the kidney and that activation of NALP3 inflammasomes in the renal function increases the salt sensitivity of arterial blood pressure resulting in sustained hypertension (Supported by NIH grants HL091464, HL75316, DK54927).