BACKGROUND: Hypertension is a known risk factor for cardiovascular diseases. In addition to environmental factors, several genetic factors are involved in its pathogenesis. In a large-scale population study (N = 4,500) transcriptomics analyses identified CRIP1 (Cysteine-rich intestinal protein 1) in human monocytes as being strongly associated with changes in blood pressure (BP). CRIP1 belongs to the LIM-domain/double zinc finger protein is upregulated in cancer but also in intestinal and immune cells. CRIP1 is co-localized to renin-producing juxtaglomerular cells in the kidney. Furthermore, a link between the CRIP1 expression and immune regulation was found. So far, the role of CRIP1 in the pathophysiology of hypertension is unknown.

AIM: The overall aim of this project is to identify the functional role of CRIP1 in hypertension. Here, specifically, we examined the association between CRIP1 gene expression and cardiovascular and kidney related traits in the population and investigated the regulation of CRIP1 expression in various experimental mice models. 

METHODS: CRIP1 expression was measured in monocytes by qPCR in 1,527 participants of the Gutenberg Health Study (GHS). Linear regression models were used to calculate the association between CRIP1 expression and related cardiovascular traits for correlations with CRIP1 mRNA Additionally CRIP1 gene expression was investigated via qPCR in hearts and kidneys of hypertensive mouse models. Briefly, C57BL/6N mice received subcutaneously implanted deoxycorticosterone acetate (DOCA) pellets and Angiotensin II (AngII) osmotic pumps for 21 days. Furthermore hypertension was induced in in C57Bl/6J mice via AngII from subcutaneously implanted osmotic pumps for 5 and 21 days. 

RESULTS: CRIP1 gene expression correlated significantly with kidney and cardiovascular related traits like urine albumin/creatinine ratio (effect size ß = 0.0577, p = 5e-10), microalbuminuria (ß = 0.0787, p = 6.8e-03), homoarginin (ß = 0.0488, p = 3.4e-05), LVPWd (ß = 0.2475, p = 9.6e-05) and risk factor current smoker (ß = - 0.0917, p = 3.2e-05). Moreover, we found a significant association of CRIP1 gene expression with body mass index (ß = 0.0078, p = 4.4e-04) and diabetes mellitus marker HbA1c (ß = 0.0439, p = 4.4e-04). In hypertensive mice models a significantly increased CRIP1 expression was found in kidneys and hearts of DOCA and AngII treated mice. Remarkably CRIP1 gene expression was significantly increased in hearts as well in short- (5 days) as long-term (21 days) AngII treated mice compared to the controls.

CONCLUSION: CRIP1 expression is associated with reduced renal function, a global player in the regulation of hypertension and correlates with cardiovascular traits. Our results point towards an important role of CRIP1 in the pathophysiology of hypertension.