ABCB1 (P-glycoprotein) but not ABCC1 (MRP1) is downregulated in peripheral blood mononuclear cells of spontaneously hypertensive rats

Abstract

Although the kidney is a major target in hypertension, several studies have correlated important immune alterations with the development of hypertension in spontaneously hypertensive rats (SHR), like increased secretion of pro-inflammatory cytokines, inflammatory infiltration in kidneys and thymic atrophy. Because adenosine-triphosphate-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) and adenosine-triphosphate-binding cassette sub-family C member 1 (ABCC1; multidrug resistance protein 1), two proteins first described in multidrug resistant tumors, physiologically transport several immune mediators and are required for the adequate functioning of the immune system, we aimed to measure the expression and activity of these proteins in peripheral blood mononuclear cells (PBMC), thymocytes, and also kidneys of normotensive Wistar Kyoto rats and SHR. Our results showed that ABCB1, but not ABCC1, activity was diminished (nearly 50%) in PBMC. Moreover, Abcb1b gene was downregulated in PBMC and kidney of SHR and this was not counterbalanced by an upregulation of its homolog Abcb1a, suggesting that the diminished activity is due to downregulation of the gene. No alteration was detected in ABCB1 activity in SHR thymocytes, indicating that this downregulation occurs after lymphocytes leave the primary lymphoid organs. Even though it is not known at present which parameter(s) is(are) responsible for this downregulation, it may contribute for the altered immune response observed in hypertension and to possible altered drug disposition in hypertensive individuals, resulting in greater drug interaction and increased drug toxicity.

Unveiling the Role of Multidrug Resistance Proteins in Hypertension

“…56 In addition, in a recent study, we showed that ABCB1, but not ABCC1, is downregulated in peripheral blood mononuclear cells and in the kidneys of spontaneously hypertensive rats. 57 Our results were confirmed by a study of another group showing that a high-salt diet reduced the expression levels of the abcb1a and abcb1b genes in the rat liver and kidney but increased their expression levels in the duodenum, jejunum, and ileum, suggesting that the regulation of this protein is tissue specific. 58 Corroborating this, it has been shown that ABCB1 undergoes tissue-specific regulation in response to the activation of the nuclear pharnesoid X receptor, because the expression of abcb1a mRNA was induced in the murine small intestine by treatment with the pharnesoid X receptor activators rifampicin and St John's wort, but its expression in the kidney was not altered.…”

Loss of constitutive <em>ABCB1</em> expression in breast cancer associated with worse prognosis

“…Such results are in agreement with the findings of Pavelic et al,50 who described ABCB1 immuno-reactivity in normal ductal epithelia using four independent antibodies. Likewise, Scala et al51 showed that >80% of normal breast ductal epithelium stained positively for ABCB1, with staining being confined to the luminal surface 51. Considering that most breast tumors have a ductal origin, it seems that ABCB1 detection in breast carcinoma is a consequence of constitutive ABCB1 expression in the breast, rather than an acquired or rare phenotype.…”

Co-expression of pregnane X receptor and ATP-binding cassette sub-family B member 1 in peripheral blood: A prospective indicator for drug resistance prediction in non-small cell lung cancer

“…Ban et al , by aid of flow cytometry, examined the ABCB1 profile of peripheral blood mononuclear cells (PBMCs) in epilepsy patients and found a higher basal ABCB1 level in them and in patients on high-dose medications ( 16 ). Valente et al investigated the downregulation of ABCB1 in the kidneys and PBMCs of SHR rats, and suggested that for hypertensive humans, assessing gene activity in PBMCs is a non-invasive, and therefore practical, test method ( 17 ).…”