The juxtaglomerular apparatus

In 1898, Tigerstedt and Bergman published the discovery of renin in Acta Physiologica (Tigersted & Bergman 1898). Already 9 years earlier, Golgi (1889) had described the anatomy of the nephron and that the nephron’s distal tubule returns to its own glomerulus. This is an invariable and preserved property in all mammals and many other different animal species. This intimate coupling between the macula densa cells and the smooth muscle – and granular cells of the afferent arteriole led early investigators (Goormaghtigh 1940) to suggest the existence of a coupling between the composition of fluid at the macula densa site and the function of the glomerular arterioles (Goormaghtigh 1940). This anatomical feature has further intrigued investigators like Thurau and Guyton to formulate more detailed theories about the importance of this mechanism for renal autoregulation, fluid excretion and release of renin (Guyton et al. 1964, Thurau 1964). It was difficult to prove the existence of a mechanism owing to the inaccessibility of these structures for direct micropuncture. However, studies by Schnermann and co-workers clearly demonstrated the existence of a tubuloglomerular feedback mechanism via changes of single nephron GFR and stop flow pressure at alterations of the fluid load to the macula densa area (Schnermann et al. 1970, 1973). There are at least two ways of signalling known, one to the arteriolar smooth muscle cells and another one to the renin producing cells in glomerular arterioles. Sodium homoeostasis is of paramount importance for blood pressure control under normal and under pathophysiological conditions (O’Neill et al. 2011, Rajapakse & Mattson 2011, Soleimani 2011, Umbach et al. 2011) and is controlled meticulously (Bachmann et al. 2011, Dantzler et al. 2011, Hoffmann & Pedersen 2011, Jankowski et al. 2011, Kuczeriszka et al. 2011, Soleimani 2011, Sorensen et al. 2011). Longterm decreases of NaCl intake lead to a reduced NaCl concentration at the macula densa site leading to renin secretion, while increases in distal delivery of NaCl will activate the tubuloglomerular feedback mechanism and contract the afferent arteriole, thereby regulating the single nephron glomerular filtration rate. This latter effect contributes importantly to the autoregulation of renal blood perfusion and filtration rate and, through theses actions, controls NaCl excretion in urine. The tubuloglomerular feedback mechanism (TGF) can be initiated only by increased NaCl concentration at the macula densa lumen in the micropuncture setting. It enhances Na/K/2Cl co-transport through the apical membrane (Persson et al. 1991). Recently, however, in isolated perfused thick ascending limb of Henle loop (TAL) it has been found an activation of the TGF system with flow but without concentration changes of sodium and chloride (Sipos et al. 2010). The reason for this discrepancy is not known. Both the long-term and the short-term mechanism co-operate so that the TGF prevents sodium loss working at a short-term scale while the renin-angiotensin system (RAS) is related to body salt balance. The RAS via angiotensin II also resets the TGF, which allows GFR stabilization at the new operating point of the TGF (Karlsen et al. 1995, Schnermann et al. 1998). The mediation of the macula densa cell activation to the afferent arteriole, the main effector in TGF, has been controversially discussed for many years. The primary idea of a metabolic control of GFR by adenosine was supported by findings of an inhibition of the TGF by specific adenosine type 1 receptor (A1) antagonists and loss of TGF in A1 knockout mice (Osswald et al. 1980, Schnermann et al. 1990, Brown et al. 2001). The observation of ATP release in stimulated macula densa cells and the reduction of TGF in ecto5′-nucleotidase/CD73-deficient mice suggested that adenosine partly origins from extracellular breakdown of ATP (Castrop et al. 2004). Angiotensin II works as a co-factor of TGF sensitizing the mechanism (Hall et al. 1985). In addition, many other systemic or locally released substances influence TGF. Among them, nitric oxide (NO) and sympathetic nerves are important modulators of the TGF. The role of renal nerves has been studied and published in Acta Physiologica in this context. While early work suggested no influence of renal nerve stimulation on TGF (Norlen et al. 1978), there is evidence from several studies for a role of renal nerves in TGF resetting (Hermansson et al. 1984, Thorup et al. 1995, 1996, Kurkus et al. 1998). The TGF pathway is also significantly modulated by NO (Braam et al. 2000, Persson & Bachmann 2000). Sources of NO in the juxtaglomerular apparatus (JGA) are the neuronal NO synthase in macula densa cells and the endothelial NOS located mainly in the endothelium of glomerular arterioles and capillaries (Persson & Bachmann 2000). In general, reduction of NO goes along with higher