Referenced in: none

Automatically associated channels: Kir2.3

Title: Increased intracellular Ca++ in the macula densa regulates tubuloglomerular feedback.

Authors: YiLin Ren, Ruisheng Liu, Oscar A Carretero, Jeffrey L Garvin

Journal, date & volume: Kidney Int., 2003 Oct , 64, 1348-55

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12969153

Abstract
Tubuloglomerular feedback is initiated by an increase in NaCl at the macula densa lumen, which in turn increases intracellular Ca++. In the present study, we examined the role of increased intracellular Ca++ in tubuloglomerular feedback and the source of the increased Ca++. We hypothesized that an increase in intracellular Ca++ at the macula densa via the basolateral Na+/Ca++ exchanger, caused by an increase in luminal NaCl, initiates Ca++-mediated Ca++ release from intracellular stores, which is essential for tubuloglomerular feedback.Rabbit afferent arterioles and attached macula densas were simultaneously microperfused in vitro. Tubuloglomerular feedback was induced by increasing macula densa Na+/Cl- from 11/10 mmol/L (low) to 81/80 mmol/L (high) and was measured before and after treatment.To investigate whether elevations in intracellular Ca++ are required for tubuloglomerular feedback, the calcium ionophore A23187 or the Ca++ chelator BAPTA-AM was added to the macula densa lumen. During the control period, tubuloglomerular feedback decreased afferent arteriole diameter from 18.1 +/- 1.1 microm to 15.3 +/- 0.8 microm. Adding 2 x 10-6 mol/L A23187 to the low NaCl macula densa perfusate induced tubuloglomerular feedback; diameter decreased from 18.0 +/- 1.0 microm to 15.4 +/- 0.9 microm (N = 6; P < 0.01). After adding BAPTA-AM (25 micromol/L) to the macula densa lumen, tubuloglomerular feedback response was completely eliminated. We next studied the source of increased macula densa Ca++ in response to increased NaCl concentration. During the control period, tubuloglomerular feedback decreased afferent arteriole diameter from 18.5 +/- 1.6 microm to 15.3 +/- 1.2 microm (N = 6; P < 0.01). After adding the Na+/Ca++ exchanger inhibitor 2'4'-dichlorobenzamil (10 micromol/L) or KB-R7943 (30 micromol/L) to the bath, the tubuloglomerular feedback response was blocked; however, the afferent arteriole response to angiotensin II or adenosine was not altered. Next, we tested the Ca++-adenosine triphosphatase (ATPase) inhibitor thapsigargin (0.1 micromol/L), which has been reported to inhibit sarcoplasmic reticulum Ca++-ATPase activity and prevent restoration of intracellular Ca++ stores. When thapsigargin was added to the macula densa lumen, it reduced the first tubuloglomerular feedback response by 33% and completely eliminated the second and third tubuloglomerular feedback responses. In the absence of thapsigargin, there was no significant decrease in the tubuloglomerular feedback responses (N = 6). Neither the L-type Ca++ channel blocker nifedipine (25 micromol/L), nor the T-type Ca++ channel blocker pimozide (10 micromol/L), inhibited tubuloglomerular feedback when added to the macula densa lumen.We concluded that (1). increased intracellular Ca++ at the macula densa is required for the tubuloglomerular feedback response; (2). Na+/Ca++ exchange appears to initiate Ca++-mediated Ca++ release from intracellular stores; and (3). luminal L-type or T-type Ca++ channels are not involved in tubuloglomerular feedback.