Effects of Furosemide and Verapamil on the NaCl Dependency of Macula Densa–Mediated Renin Secretion

Abstract

The present studies in perfused specimens of the juxtaglomerular apparatus microdissected from rabbit kidneys were performed to quantitatively evaluate the relation between macula densa NaCl concentration and renin secretion and to study the effect of furosemide and verapamil on NaCl dependency of renin release. Renin secretion was found to decrease exponentially when macula densa NaCl concentration was increased from 26/7 mmol/L (Na/Cl) to 46/27, 66/47, and 86/67 mmol/L. Increasing Na/Cl concentrations from 86/67 to 106/87 mmol/L had no further effect on renin secretion. [Cl]1/2, the chloride concentration producing the half-maximal effect, was 30 mmol/L. Addition of 50 mumol/L furosemide to the luminal fluid caused renin secretion to become essentially independent of macula densa NaCl concentration. This effect was due to both an increase of renin secretion at high NaCl concentrations and a decrease of renin release at low NaCl concentrations. Verapamil added to the superfusate at a concentration of 1 mumol/L also abolished NaCl dependency of renin secretion; most of this effect was due to an increase of renin release at high luminal NaCl. These results suggest that Na-2Cl-K cotransport and calcium flux through voltage-gated channels are two mechanisms required for the expression of NaCl-dependent renin release. Identification of the cellular localizations of these two critical membrane proteins in the renin control pathway requires further study.

Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells

“…Importantly, not only a single large change in luminal NaCl delivery (Figure 3a), but also more subtle reductions in [NaCl] L in the physiological range (Figure 5a (Figure 5b). These findings are not only consistent with earlier work (27), but the data are essentially identical to the previously established [Cl] 1/2 , the luminal chloride concentration producing a half-maximal renin secretory effect (27).…”

“…Inhibition of MD Na:2Cl:K cotransport with furosemide prevented [NaCl] L -dependent increases in HEK/EP 1 [Ca 2+ ] i (Figure 3b), consistent with earlier findings that furosemide blocks MD NaCl transport dependency of renin release (27). Low distal tubular [NaCl] is associated with states of volume depletion and is a stimulus for MD signaling that increases synthesis and release of renin from juxtaglomerular granular cells (3)(4)(5)(6).…”

Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and the glomerular afferent arteriole.

“…Additionally, this Cl Ϫ sensing pathway from BSC1 in the macula densa to BSC2 in the extraglomerular mesangium and the afferent arteriole may be important in renin secretion which is activated by a decrease in [Cl Ϫ ] in the CTAL (30). Both TGF and renin release are known to be inhibited by furosemide (31)(32)(33). Although this inhibitory effect of furosemide may take place through the macula densa apical Na-K2Cl cotransporter (BSC1), it is also possible that TGF and renin release are inhibited by furosemide acting on the BSC2 isoform in the extraglomerular mesangium and/or the afferent arteriole.…”

Thick Ascending Limb of the Loop of Henle

“…NKCC2 is also expressed in macula densa cells (4) (Figure 1), which are known to demonstrate apical Na 1 -K 1 -2Cl 2 cotransport activity (12). Luminal loop diuretics applied at the macula densa block both tubuloglomerular feedback (13) and the suppression of renin release by luminal Cl 2 (14), indicating that NKCC2 in the macula densa functions as the tubular sensor for both processes. The ability of loop diuretics to block tubuloglomerular feedback has been linked to their greater renal functional tolerance versus thiazides in advanced CKD (15).…”