Aldosterone Blunts Tubuloglomerular Feedback by Activating Macula Densa Mineralocorticoid Receptors

Abstract

Chronic aldosterone administration increases glomerular filtration rate (GFR) while inhibition of mineralocorticoid receptors (MR) markedly attenuates glomerular hyperfiltration and hypertension associated with primary aldosteronism or obesity. However, the mechanisms by which aldosterone alters GFR regulation are poorly understood. In the present study, we hypothesized that aldosterone suppresses tubuloglomerular feedback (TGF) via activation of macula densa (MD) MR. First, we observed the expression of MR in MD cells isolated by laser capture microdissection (LCM) and by immunofluorescence in rat kidneys. Second, to investigate the effects of aldosterone on TGF in vitro, we microdissected the juxtaglomerular apparatus (JGA) from rabbit kidneys and perfused the afferent arteriole (Af-Art) and distal tubule simultaneously. Under control conditions, TGF was 2.8 ± 0.2µm. In the presence of aldosterone (10−8 mol/L), TGF was reduced by 50%. The effect of aldosterone to attenuate TGF was blocked by the MR antagonist eplerenone (10−5 mol/L). Third, to investigate the effect of aldosterone on TGF in vivo, we performed micropuncture and TGF was determined by maximal changes in stop-flow pressure Psf (ΔPsf) when tubular perfusion rate was increased from 0 to 40 nl/min. Aldosterone (10−7 mol/L) decreased ΔPsf from 10.1 ± 1.4 to 7.7 ± 1.2 mmHg. In the presence of L-NG-monomethyl arginine citrate (L-NMMA, 10−3 mol/L), this effect was blocked. We conclude that MR are expressed in MD cells and can be activated by aldosterone, which increases nitric oxide (NO) production in the MD and blunts the TGF response.

Interaction between nitric oxide and superoxide in the macula densa in aldosterone-induced alterations of tubuloglomerular feedback

“…As shown in Fig. 2A, when NaCl concentration in tubular perfusate was increased from 10 to 80 mmol/l, the Af-Art In the presence of aldosterone (10 Ϫ7 mol/l) in tubular perfusate, the AfArt diameter decreased from 17.6 Ϯ 0.5 to 16.1 Ϯ 0.6 m and the TGF response was reduced to 1.4 Ϯ 0.2 m (n ϭ 5, P Ͻ 0.05), indicating that aldosterone blunts TGF response, similar to our recent findings (12).…”

“…We reported recently that aldosterone blunts the TGF response (12). Activation of MR by aldosterone enhanced both NO (12) and O 2 Ϫ (46) production in the MD.…”

“…Activating MR in the macula densa blunted TGF response both in vivo and in vitro by enhancing NO generation (12). These findings provide a novel mechanism for regulation of renal hemodynamics and salt-water balance by aldosterone, especially the hyperfiltration in primary aldosteronism and obesity patients.…”

“…Activation of MR by aldosterone enhanced both NO (12) and O 2 Ϫ (46) production in the MD. Therefore, the interaction between NO and O 2 Ϫ is important in regulation of TGF response and control of renal hemodynamics.…”

“…Responsiveness of TGF can be regulated by a number of factors, including ANG II (44), adenosine (40), arachidonic acid metabolites (24), ATP (22,36), atrial natriuretic factor (21), NO (30), and O 2 Ϫ (31). Recently, we found that aldosterone plays an important role in control of TGF response (12).…”