Effects of diabetes and SGLT2 inhibition on nephron hemodynamics. In the diabetic nephron, overexpression and compensatory upregulation of the activity of SGLT2 glucose and sodium reabsorption in the proximal convoluted tubule results in decreased delivery of solutes to the macula densa. The resulting reduction in solute and water transport into the tubular epithelial cells reduces adenosine triphosphate (ATP) release from the basolateral membrane of tubular epithelial cells, which in turn reduces adenosine production and activation of the A1 receptor expressed in the afferent arteriole with a net effect of vasodilation. In the diabetic nephron with SGLT inhibition, lessening SGLT2-driven sodium-coupled glucose transport in the proximal convoluted tubule normalizes solute delivery to the macula densa, increasing solute and water reabsorption and increasing basolateral release of ATP from the tubular epithelium. The resulting increase in adenosine activation of the A1 adenosine receptor reverses afferent arteriole vasodilation associated with diabetic kidney disease. Figure 2 from Alicic, AJKD © National Kidney Foundation.