Interactions between adenosine, angiotensin II and nitric oxide on the afferent arteriole influence sensitivity of the tubuloglomerular feedback

Abstract

Adenosine, via activation of A1 receptors on the afferent arteriole (AA), mediates the tubuloglomerular feedback (TGF) mechanism. Angiotensin II and nitric oxide (NO) can modulate the sensitivity of the TGF mechanism. However, the interaction among these substances in regulating the TGF resetting phenomenon has been debated. Studies in isolated perfused AA have shown a biphasic response to accumulating doses of adenosine alone. In the nanomolar range adenosine has a weak contractile effect (7%), whereas vasodilatation is observed at high concentrations. However, a synergistic interaction between the contractile response by adenosine and that of angiotensin II has been demonstrated. Adenosine in low concentrations strongly enhances the response to angiotensin II. At the same time, angiotensin II in physiological concentrations increases significantly the contractile response to adenosine. Moreover, addition of a NO donor (spermine NONOate) to increase NO bioavailability abolished the contractile response from combined application of angiotensin II and adenosine. These mutual modulating effects of adenosine and angiotensin II, and the effect of NO on the response of AA can contribute to the resetting of the TGF sensitivity.The tubuloglomerular feedback (TGF) is a negative-feedback system operating within the juxtaglomerular apparatus that can regulate glomerular filtration rate (GFR) by changing arteriolar resistance and hence blood flow and pressure into the glomerular capillaries. In this control system the tubular load to the distal parts of the nephron is detected via changes in tubular sodium chloride concentration at the macula densa site. This information is then used to determine the contractile state of the afferent arteriole (AA) that is the main effector link of this controller. The sensitivity and reactivity of the TGF system can be modulated via several different factors and via those changing the effector response. Exactly where and how this modulation of the TGF response occurs has not been clear. Recent work from our laboratory has indicated that this modulation to some extent can be carried out by the arterioles themselves.Figure 1A shows signaling pathways of the TGF activated by an increase in NaCl delivery to the macula densa site. Evidence from our laboratory and others indicate that increased NaCl delivery leads to depolarization of the basolateral membrane of the macula densa cells, activation of nitric oxide synthases (NOS) to produce NO, and also activation of NADPH oxidase to produce superoxide (Persson et al., 1991; Liu et al., 2002; Liu and Persson, 2004). This activation of macula densa also leads to release of ATP, possibly via swelling of the macula densa cells that occur following increased uptake of NaCl (Gonzalez et al., 1988a,b). © 2013 Persson, Lai, Gao, Carlström and Patzak.