Macula densa signalling—a potential role of cyclooxygenase‐2 (COX‐2)? (2000)

Introduction Is there a role for COX-2 in regulating renin expression and release? Prostaglandins are mediators of vascular tone and salt and water homeostasis in the mammalian kidney; their Following chronic salt depletion, COX-2 expression in regulation of glomerular haemodynamics and distal the macula densa and peri-macula densa region nephron function has been well described. Renin proincreased significantly [3]. This finding suggested that duction and release is also known to be mediated by prostaglandins generated by macula densa COX-2 prostaglandins generated by afferent arteriole and by might be involved in mediating renin release in prostaglandin-dependent signalling from the macula response to volume depletion. densa [1]. In the mammalian kidney, the macula densa is There are two separate gene products with cycloinvolved in regulating renin release by sensing alteraoxygenase activity, cyclooxygenase-1 (COX-1) and tions in luminal chloride via changes in the rate cyclooxygenase-2 (COX-2). The gene for COX-1, the of Na+/K+/2Cl− cotransport. Inhibition of constitutive prostaglandin G2/H2, encodes a Na+/K+/2Cl− cotransport with loop diuretics results 2.7–2.9 kb transcript, while the gene for COX-2, the in a decrease in chloride reabsorption by the macula ‘inducible’ prostaglandin G2/H2 synthase, encodes a densa and an increase in renin secretion [3]. It has 4.2–4.5 kb transcript, which increases in response to long been recognized that non steroidal antiinflammatory or mitogenic stimuli. In the kidney, inflammatory drug (NSAID) administration can elicit constitutive prostaglandin G2/H2 synthase (COX-1) a hyporeninaemic state, and studies using an isolated has been localized to mesangial cells, arteriolar endoperfused juxtaglomerular preparation indicated that thelial cells, parietal epithelial cells of Bowman’s capNSAID administration prevented the increases in renin sule and cortical and medullary collecting ducts [2,3]. release mediated by macula densa sensing of decreases in luminal NaCl [4]. Immunoreactive COX-1 cannot be detected in cortical thick limb or macula densa. What is the expression of COX-2 in the kidney? Harding et al. [5] first demonstrated a direct role for macula densa COX-2 activity in mediating renin production and release by showing that NS398, a There is also localized expression of COX-2 in the selective COX-2 inhibitor, inhibited increases in renal developing and adult kidney. Using in situ hybridizarenin expression in response to a low-salt diet. Our tion and immunohistochemical localization, we have group has subsequently demonstrated that increases in documented that COX-2 expression is localized to two renin mRNA expression and renal renin activity in cell types in normal adult rat kidney: (i) occasional response to angiotensin-converting enzyme (ACE) macula densa cells and surrounding cTALH cells; and inhibition were also blunted by the highly selective (ii) a subset of medullary interstitial cells near the COX-2 inhibitor, SC59236 [6 ]. We have further shown papillary tip [3]. In the cortex, the immunoreactivity that in experimental renovascular hypertension, in of stained cells was intense, but only one (and rarely which macula densa COX-2 expression is increased two) COX-positive cells were observed per site. No COX-2 immunoreactivity was detected in arterioles, [7,8], COX-2 inhibition blunted increases in renin glomeruli or cortical or medullary collecting ducts. expression and lowered blood pressure [8]. In addition, our preliminary results have indicated that in COX-2 knockout mice, renal renin activity did not increase in response to ACE inhibition [9]. Direct evidence for a Correspondence and offprint requests to: R. C. Harris MD, Division role for COX-2 has recently been provided by Traynor of Nephrology, Department of Medicine, S-3223 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. et al. [10], who determined that in an isolated perfused