Fig. 6.

Proposed deleterious role for Na⁺-glucose cotransporter SGLT1-mediated reabsorption during recovery from ischemia-reperfusion (IR)-induced acute kidney injury. IR initially suppresses SGLT2 and SGLT1-mediated reabsorption in the early and later proximal tubule, respectively, which is associated with glucosuria. Early recovery of SGLT1-mediated Na⁺ reabsorption in late proximal tubule/outer medulla sustains IR-induced hypoxia. This enhances cell injury in the outer medulla and further inhibits Na⁺-K⁺-2Cl^– cotransporter (NKCC2)-mediated NaCl reabsorption in the thick ascending limb, which impairs urine concentration and enhances NaClK delivery to the macula densa ([Na/Cl/K]_MD). The latter reduces renin expression and lowers glomerular filtration rate (GFR) via tubuloglomerular feedback. The reduction in GFR enhances plasma creatinine and urea, with the latter contributing to enhanced plasma osmolality. The increased hypoxia and cell injury further enhances mitochondrial dysfunction, inflammation, and fibrosis, which can spread to the cortex and further suppress tubular function. A sustained suppression of SGLT2 maintains a high glucose load to SGLT1, thereby sustaining the detrimental influence of SGLT1. Kim-1, kidney injury molecule-1; Epo, erythropoietin; Col1a1, collagen type I-α₁; Fn1, fibronectin 1; Ccl2, chemokine (C-C motif) ligand 2; Ppargc1a, peroxisome proliferator-activated receptor-γ coactivator-1α.