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. 2022 Sep 29;7(12):2589–2607. doi: 10.1016/j.ekir.2022.09.018

Figure 1.

Figure 1

Glucose reabsorption by SGLT1 and SGLT2 in normal and diabetic kidney. (a) Glucose reabsorption by sodium/glucose cotransporter 2 (SGLT2) is a low-affinity, high-capacity glucose trans=porter, is expressed apically in epithelial cells of the proximal convoluted tubule and accomplishes reabsorption of approximately 90% of filtered glucose. Approximately 10% of glucose that escapes reabsorption by SGLT2 is subsequently resorbed by high-affinity low-capacity SGLT1, which is expressed apically in epithelial cells of the straight descending proximal tubule. To provide the energy required to drive glucose transport against its concentration gradient, both SGLT2 and SGLT1 couple glucose transport across the apical cell membrane to the electrochemical gradient generated by active sodium-potassium transport via the Na+/K+-ATPase pump located on the basolateral membrane of the proximal tubule. Na+/K+-ATPase pump drives Na+ exchange for K+ removing Na+ out of cell, generating adenosine in this process. Adenosine acts in paracrine manner to constrict afferent arteriola maintaining glomerular hemodynamics. As the intracellular concentration of Na+ decreases, this ion moves passively with glucose from the tubular lumen to the intracellular space via SGLT2 and SLGT1. Once in the cellular lumen, the passively concentration gradient translocates reabsorbed glucose into the interstitial space via glucose cotransporters. (b) In the diabetic nephron increased proximal tubular reabsorption of glucose and sodium chloride by SGLT1 and SGLT2 leads to decreased solute delivery to the macula densa in the distal convoluted tubule. As a result of reduced concentration of sodium chloride, adenosine triphosphatase activity at the macula densa is reduced with a consequent reduction in adenosine generation. Reduced production of adenosine leads to afferent arteriolar vasodilation that drives glomerular hyperperfusion and hyperfiltration. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphatse; GC, glomerular capillary; K+, pottassium; Na+, sodium; NaCl, sodium chloride. Reprinted with permission from Alicic RZ, Johnson EJ, Tuttle KR. SGLT2 inhibition for the prevention and treatment of diabetic kidney disease: a review. Am J Kidney Dis. 2018;72:267–277.