Fluid flow through the kidney nephron is being kept within a narrow range under healthy conditions for optimal maintenance of salt and water balance. The macula densa cells control the tubuloglomerular feedback (TGF) to fine-tune GFR [156]. As shown in Fig. 7, when the luminal NaCl concentration at the macula densa rises, as during ECV expansion or in response to SGLT2 inhibition, NaCl entry into macula densa cells via NKCC2 leads to the production of adenosine. The macula densa cells do not have enough Na+/K+-ATPases on their basolateral surface to excrete the added Na+ taken up. This results in osmotic swelling and the current concept is that the swelling leads to exit of ATP across the basolateral membrane via stretch-activated, non-selective maxi-anion channels, followed by its conversion to adenosine via the ecto-5′-nucleotidase channels [16, 87, 143, 144]. Adenosine then interacts with adenosine 1 receptors (A1R) on vascular smooth muscle, resulting in contraction of afferent arterioles and reduction of GFR (the TGF response). On the other hand, in response to decreased luminal NaCl concentration at the macula densa (the reverse situation illustrated in Fig. 8), i.e., in the context of reduced blood pressure or glomerular filtration, NKCC2 transport activity is reduced, which causes release of prostaglandin in macula densa that activates signaling cascades to promote renin release and activation of the renin-angiotensin-aldosterone system (RAAS). This in turn increases the blood pressure via aldosterone by increasing renal reabsorption of sodium and water. In addition, with luminal NaCl concentrations below the threshold value, vasodilation of afferent arterioles occurs, which increase glomerular filtration pressure and tubular fluid flow.