Fig. 1.

Left: with reduced perfusion pressure, a low macula densa chloride concentration stimulates the release of renin and local prostaglandins, which serve to maintain glomerular filtration rate (GFR) by afferent vasodilatation and efferent vasoconstriction. Right: excess chloride from normal saline and/or hyperchloremia increases distal chloride delivery to the macula densa, signaling a decrease in GFR from afferent vasoconstriction, mediated by thromboxane and adenosine, and attenuation of efferent vasoconstriction from reduced renin and angiotensin II levels. In the macula densa, influx of chloride via NKCC2 increases intracellular chloride and subsequent basolateral chloride exit with ATP. In, juxtaglomerular (JG) cells, angiotensin II increases intracellular calcium, which triggers chloride efflux through calcium-activated chloride channels, leading to cell depolarization and inhibition of renin release. Calcium-activated chloride channels are also present in mesangial cells and afferent arteriole smooth muscle cells (AASMC), where they are under the influence of multiple vasoconstrictors acting through G protein-coupled receptors. However, unlike in JG cells, chloride efflux-mediated cell depolarization triggers calcium influx through voltage-dependent calcium channels, leading to robust cell contraction. COX2, cyclooxygenase 2; PGE₂, prostaglandin E₂. [Printed with permission from Mount Sinai Health System.]