Original Articles - Renal Physiopathology

The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

Figueroa S.M., Bertocchio J., Nakamura T., El-Moghrabi S., Jaisser F. and Amador C.A. Pharmaceutics. 2023; 15(5):1373.

Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells…

α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions

Guerrero A., Visniauskas B., Cárdenas P., Figueroa S.M., Vivanco J., Salinas-Parra N., Araos P., Nguyen Q.M., Kassan M., Amador C.A., Prieto M.C. and Gonzalez A.A. Frontiers in Cardiovascular Medicine. 2021; 8:644797.

Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb’s cycle is in a state of suppression in most tissues. However, …

Upregulation of Cortical Renin and Downregulation of Medullary (Pro) Renin Receptor in Unilateral Ureteral Obstruction

Figueroa S.M., Lozano M., Lobos C., Hennrikus M.T., Gonzalez A.A., Amador C.A. Frontiers in Pharmacology. 2019; 14(10):1314. PMID: 31803050

Chronic kidney disease (CKD) is characterized by renal dysfunction, which is a common feature of other major diseases, such as hypertension and diabetes. Unilateral ureteral obstruction (UUO) has been used as a model of CKD in experimental animals and consists of total obstruction of one kidney ureter. The UUO decreases renal blood flow, which promotes the synthesis of renin in the juxtaglomerular apparatus…

Dendritic cells are crucial for cardiovascular remodeling and modulate neutrophil gelatinase- associated lipocalin expression upon mineralocorticoid receptor activation

Araos P., Prado C., Lozano M., Figueroa S., Espinoza A., Berger T., Mak T., Jaisser F., Pacheco R., Michea L., Amador C.A. Journal of Hypertension. 2019; 37(7):1482-1492. PMID: 31033725

Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage…

Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration

Amador C., Bertocchio J.P., André-Grégoire G., Placier S., Duong Van Huyen J.P., El Moghrabi S., Berger S., Warnock D., Chatziantoniou C., Jaffe I., Rieu P., Jaisser F.. Kidney International. 2016; 89(2): 354-62. PMID: 26422501

Calcineurin inhibitors such as cyclosporine A (CsA) are still commonly used after renal transplantation, despite CsA–induced nephrotoxicity (CIN), which is partly related to vasoactive mechanisms. The mineralocorticoid receptor (MR) is now recognized as a key player in the control of vascular tone, and both endothelial cell- and vascular smooth muscle cell (SMC)-MR modulate the vasoactive responses to vasodilators and …

Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes.

Amador C.A., Barrientos V., Peña J., Herrada A.A., González M., Valdés S., Carrasco L., Alzamora R., Figueroa F., Kalergis A.M., Michea L. Hypertension. 2014; 63(4): 797-803. PMID: 24420551

Adaptive immune response has been implicated in inflammation and fibrosis as a result of exposure to mineralocorticoids and a high-salt diet. We hypothesized that in mineralocorticoid-salt–induced hypertension, activation of the mineralocorticoid receptor alters the T-helper 17 lymphocyte (Th17)/regulatory T-lymphocyte/interleukin-17 (IL-17) pathway, contributing to cardiac and renal damage. We studied the …

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

Tarjus A., Martínez E., Amador C., Latouche C., El Moghrabi S., Berger T., Wah Mak T., Fay R., Farman N., Rossignol P., Zannad F., López N., Jaisser F. Hypertension. 2015; 66(1): 158-66. PMID: 25987661

Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase–associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of …

Neutrophil Gelatinase-Associated Lipocalin from immune cells is mandatory for aldosterone-induced cardiac remodeling and inflammation

Buonafine M., Martínez-Martínez E., Amador C, Gravez B., Ibarrola J., Fernández-Celis A., El Moghrabi S., Rossignol P., López-Andrés N., Jaisser F. Journal of Molecular and Cellular Cardiology. 2018; 115:32-38. PMID: 29289651.

Immune system activation is involved in cardiovascular (CV) inflammation and fibrosis, following activation of the mineralocorticoid receptor (MR). We previously showed that Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a novel target of MR signaling in CV tissue and plays a critical role in aldosterone/MR-dependent hypertension and fibrosis. We hypothesized that the production of NGAL by immune cells may play an important part in the …

Myeloid CD11c+ Antigen-Presenting Cells Ablation Prevents Hypertension in Response to Angiotensin II Plus High-Salt Diet.

Hevia D., Araos P., Prado C., Fuentes Luppichini E., Rojas M., Alzamora R., Cifuentes-Araneda F., González A., Amador C.A., Pacheco R., Michea L. Hypertension. 2018; 71(4):709-718. PMID: 29378857.

Increasing evidence shows that antigen-presenting cells (APCs) are involved in the development of inflammation associated to hypertension. However, the potential role of APCs in the modulation of renal sodium transport has not been addressed. We hypothesized that APCs participate in renal sodium transport and, thus, development of high blood pressure in response to angiotensin II plus a high-salt diet. Using transgenic mice that allow the …

Aldosterone Promotes Autoimmune Damage by Enhancing Th17-Mediated Immunity

Herrada A.A., Contreras F.J., Marini N.P., Amador C.A., González P.A., Cortés C.M., Riedel C.A., Carvajal C.A., Figueroa F., Michea L.F., Fardella C.E., Kalergis A.M. J Immunol. 2010; 184(1): 191-202. PMID: 19949098

Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of …