Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor–dependent pathway

Abstract

Hypertension is a leading contributor to cardiovascular mortality worldwide. Despite this, its underlying mechanism(s) and the role of excess salt in cardiorenal dysfunction are unclear. Previously, we have identified cross-talk between mineralocorticoid receptor (MR), a nuclear transcription factor regulated by the steroid aldosterone, and the small GTPase Rac1, which is implicated in proteinuric kidney disease. We here show that high-salt loading activates Rac1 in the kidneys in rodent models of salt-sensitive hypertension, leading to blood pressure elevation and renal injury via an MR-dependent pathway. We found that a high-salt diet caused renal Rac1 upregulation in salt-sensitive Dahl (Dahl-S) rats and downregulation in salt-insensitive Dahl (Dahl-R) rats. Despite a reduction of serum aldosterone levels, salt-loaded Dahl-S rats showed increased MR signaling in the kidneys, and Rac1 inhibition prevented hypertension and renal damage with MR repression. We further demonstrated in aldosterone-infused rats as well as adrenalectomized Dahl-S rats with aldosterone supplementation that salt-induced Rac1 and aldosterone acted interdependently to cause MR overactivity and hypertension. Finally, we confirmed the key role of Rac1 in modulating salt susceptibility in mice lacking Rho GDP-dissociation inhibitor α. Therefore, our data identify Rac1 as a determinant of salt sensitivity and provide insights into the mechanism of salt-induced hypertension and kidney injury.

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

“…Pharmacological inhibitors of Rho-kinase have been shown to ameliorate proteinuria and/or kidney functions in a variety of animal models of kidney diseases, including puromycin aminonucleoside nephrosis (50,51) and hypertensive glomerulosclerosis (52)(53)(54)(55)(56). These effects were independent of systemic blood pressure, suggesting that the inhibitors act directly in the kidney, in particular on podocytes (52)(53)(54)(55)(56). These findings support the notion that RhoA activation has a negative impact on podocyte morphology and function.…”

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

“…Renal tubule–specific MR knockout mice show significant sodium and body weight losses with a low‐salt diet 6, 7. In contrast, overactivated MR in the kidneys induces salt‐sensitive hypertension, characterized by an increase in BP in response to increased sodium intake 8. The elevated BP associated with overactivated MR is known as mineralocorticoid hypertension 9.…”

“…Furthermore, it is not clear how intestinal MR contributes to sodium dynamics and BP regulation. Most studies of MR using hypertensive models apply aldosterone/salt treatment to induce hypertension, and either aldosterone or high salt loading alone is considered insufficient for significant BP elevation 8, 25, 26. These studies suggest the significance of excessive sodium retention in hypertension via MR activation.…”

Salt intake in a sample of adult population of Novi Sad

“…Rac1 receptori u paradoksalnom odgovoru mineralokortikoidnih receptora na opterećenje solju kod kod krvnog pritiska osetljivog na so (118) Novine u ovoj oblasti ukazuju na značaj aktivacije mineralokortikoidnih receptora (Rac1-MR i beta2…”

“…Izvor: preuzeto i prilagođeno iz Shibata, 2011 Gojazne osobe sa metaboličkim sindromom često pridruženo razviju uz so osetljiv krvni pritisak i mikroalbuminuriju, poremećaje srčanog rada, povećanu koncentraciju aldosterona. Kako prevelik unos soli, tako i gojaznost, aktiviraju Rac1 i mineralokortikoidne (aldosteronske) receptore koji imaju ključnu ulogu u razvoju osetljivosti krvnog pritiska na so i renalnog oštećenja (119).…”