Glucose transporters in the kidney in health and disease

Abstract

The kidneys filter large amounts of glucose. To prevent the loss of this valuable fuel, the tubular system of the kidney, particularly the proximal tubule, has been programmed to reabsorb all filtered glucose. The machinery involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane and the facilitative glucose transporter GLUT2 on the basolateral membrane. The proximal tubule also generates new glucose, particularly in the post-absorptive phase but also to enhance bicarbonate formation and maintain acid-base balance. The glucose reabsorbed or formed by the proximal tubule is primarily taken up into peritubular capillaries and returned to the systemic circulation or provided as an energy source to further distal tubular segments that take up glucose by basolateral GLUT1. Recent studies provided insights on the coordination of renal glucose reabsorption, formation, and usage. Moreover, a better understanding of renal glucose transport in disease states is emerging. This includes the kidney in diabetes mellitus, when renal glucose retention becomes maladaptive and contributes to hyperglycemia. Furthermore, enhanced glucose reabsorption is coupled to sodium retention through the sodium-glucose cotransporter SGLT2, which induces secondary deleterious effects. As a consequence, SGLT2 inhibitors are new anti-hyperglycemic drugs that can protect the kidneys and heart from failing. Recent studies discovered unique roles for SGLT1 with implications in acute kidney injury and glucose sensing at the macula densa. This review discusses established and emerging concepts of renal glucose transport, and outlines the need for a better understanding of renal glucose handling in health and disease.

Keywords: Diabetic nephropathy; GLUT1; Gluconeogenesis; Glucose transport; SGLT1; SGLT2 inhibition.

Fig. 1

Glucose reabsorption in the kidney. a Under normoglycemia, SGLT2 in the early proximal tubule reabsorbs ~ 97% of filtered glucose. The remaining ~ 3% of glucose is reabsorbed by SGLT1 in the late proximal tubule, such that urine is nearly free of glucose. SGLT2 inhibition shifts glucose reabsorption downstream and unmasks the glucose reabsorption capacity of SGLT1 (~ 40% of filtered glucose, depending on glucose load; see numbers in parentheses). b Cell model of glucose transport: The basolateral Na⁺-K⁺-ATPase lowers cytosolic Na⁺ concentrations and generates a negative interior voltage, thereby providing the driving force for Na⁺-coupled glucose uptake through SGLT2 and SGLT1 across the apical membrane. The facilitative glucose transporter GLUT2 mediates glucose transport across the basolateral membrane down its chemical gradient. Basolateral GLUT1 may contribute to reabsorb glucose or take glucose up from peritubular space. Na⁺-glucose cotransport is electrogenic and accompanied by paracellular Cl⁻ reabsorption or transcellular K⁺ secretion to stabilize membrane potential; K⁺ channels KCNE1/unknown α subunit and KCNE1/KCNQ1 in early and late proximal tubule, respectively. This figure was modified from [178]

Fig. 2

Tubular glucose reabsorption can be saturated. Tubular reabsorption of glucose increases linearly with the filtered glucose load until reabsorption reaches the maximum tubular reabsorption (T_max glucose) and glucose starts to appear in urine. Theoretically in humans, a T_max of ~ 350 mg/min and normal GFR would result in a plasma glucose threshold of ~ 280 mg/dL. The T_max, however, varies between individual nephrons and, therefore, low level spilling of glucose into the urine initiates at modestly elevated plasma glucose levels of ~ 180–200 mg/dL in a healthy adult (see “splay”). Normoglycemia is defined as fasted plasma glucose levels < 100 mg/dL (< 5.5 mM). SGLT2 inhibition reduces the renal glucose reabsorption to the transport capacity of SGLT1, i.e., it reduces the renal glucose threshold (~ 55–65 mg/dL) and T_max (~ 60–80 mg/min)

Fig. 3

Defining the contribution of SGLT2 and SGLT1 to renal glucose reabsorption. a Left two panels: free-flow collections of tubular fluid was performed by micropuncture to establish a profile for fractional reabsorption of glucose versus fractional reabsorption of fluid along accessible proximal tubules at the kidney surface. Glucose reabsorption is prevented in the early proximal tubule in mice lacking SGLT2 (Sglt2−/−), but enhanced in the later proximal tubule, suggesting compensation by SGLT1. Right panel: in renal inulin clearance studies, the reduction in fractional renal glucose reabsorption in Sglt2−/− mice correlated with the amount of filtered glucose. b In metabolic cage studies, the SGLT2 inhibitor empagliflozin dose-dependently increased glucose excretion in WT mice. The response curve was shifted leftward and the maximum response doubled in Sglt1−/− mice. The difference between the 2 dose-response curves reflects glucose reabsorption via SGLT1 in WT mice. Glucosuria is initiated in WT mice when SGLT1-mediated glucose uptake is maximal (red arrow). The difference between curves was maintained for all higher doses (same length of vertical green lines), indicating selectivity of the drug for SGLT2 versus SGLT1 in this dose range. c Using genetic knockout models and pharmacologic tools in renal inulin clearance studies indicated that the glucose reabsorption preserved during SGLT2 knockout or inhibition (~ 40%) is mediated by SGLT1. The SGLT2 inhibitor empagliflozin was applied at low and high doses to establish free plasma concentrations (similar to concentrations in glomerular filtrate) close to IC₅₀ for mouse SGLT2 (~ 1–2 nM) or 10-fold higher. Data taken from [142, 193]

Fig. 4

Coordination of glucose transport and gluconeogenesis in the proximal tubule. (1) Insulin is a physiological stimulator of SGLT2, which may serve to maximize renal glucose reabsorption capacity in situations of increased blood glucose levels, e.g., following a meal. (2) At the same time, enhanced Na⁺-glucose uptake and insulin suppress renal gluconeogenesis. (3) The latter, in contrast, is stimulated in the post-absorptive phase (fasting) by increased catecholamine and reduced insulin levels, and involves primarily lactate as a precursor. (4) The newly formed glucose is delivered to the systemic circulation by basolateral GLUT2. (5) In metabolic acidosis, the increase in gluconeogenesis from glutamine is linked to the formation of (i) ammonium (NH₄⁺), a renally excreted acid equivalent, and (ii) new bicarbonate, which is taken up into the circulation. The Na⁺-H⁺-exchanger NHE3 contributes to apical H⁺/NH₄⁺ secretion and Na⁺/bicarbonate reabsorption. (6) The newly formed glucose can be used as fuel for proximal tubule H⁺ secretion or, after intercellular transfer, for intercalated cell H⁺ secretion. (7) SGLT2 and NHE3 are both stimulated by insulin to enhance Na⁺ and glucose reabsorption and their functions may be positively linked through the scaffolding protein MAP17

Fig. 5

Regulation of proximal tubule glucose transporters in disease. (1) Hyperglycemia enhances filtered glucose and, via SGLT2 (and SGLT1, not shown), the reabsorption of glucose and Na⁺ in the proximal tubule. (2) Diabetes can increase the renal membrane expression of SGLT2; proposed mechanisms include tubular growth, angiotensin II (Ang II), and hepatocyte nuclear factor HNF-1α, which may respond to basolateral hyperglycemia sensed through GLUT2. (3) Hyperinsulinemia and tubular growth may induce a coordinated upregulation of proximal tubular transport systems, including SGLT2, NHE3, URAT1, and Na⁺/K⁺-ATPase. The resulting increase in proximal tubular Na⁺ retention enhances GFR via tubuloglomerular feedback (TGF), which by increasing brush border torque may further increase luminal membrane transporter density in the early proximal tubule. (4) Diabetes, in part due to the associated acidosis, can enhance gluconeogenesis in the early proximal tubule. The resulting increase in intracellular glucose may feedback inhibit on SGLT2 expression. (5) HNF-1α and HNF-3β upregulate GLUT2, the basolateral exit pathway of glucose. (6) The relevance of apical translocation of GLUT2 in diabetes remains to be determined, but may be secondary to excessive SGLT2-mediated glucose uptake. (7) Increased glucose reabsorption maintains hyperglycemia. Induction of TGFβ1 and tubular growth may be particularly sensitive to basolateral glucose uptake via GLUT1. (8) Hypoxia induced by kidney injury or due to diabetes-induced hyperreabsorption may induce HIF1alpha, which inhibits apical transporters (not shown) and facilitates basolateral glucose uptake and a metabolic shift to glycolysis

Fig. 6

A proposed deleterious role for SGLT1-mediated reabsorption during recovery from 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 expression and SGLT1-mediated sodium reabsorption in late proximal tubule/outer medulla sustain IR-induced hypoxia. This sustains cell injury in the outer medulla and the inhibition of NKCC2-mediated NaCl reabsorption in the TAL, which impairs urine concentration and enhances Na-Cl-K delivery to macula densa ([Na-Cl-K]_MD). The latter reduces renin expression and lowers GFR via tubuloglomerular feedback. The reduction in GFR enhances plasma creatinine and urea, the latter contributing to enhanced plasma osmolality. The sustained hypoxia and cell injury further enhances mitochondrial dysfunction, inflammation, and fibrosis, which can spread to the cortex and further suppress tubular function. Sustained suppression of SGLT2 maintains a high glucose load to downstream SGLT1, which may enhance the detrimental influence of SGLT1. This figures was modified from [119]

Fig. 7

The tubular hypothesis of diabetic glomerular hyperfiltration. a, b In vivo micropuncture studies in rats with superficial glomeruli were performed in non-diabetic and streptozotocin diabetic rats [187]. Small amounts of blue dye were injected into Bowman space to determine nephron configuration, including the first proximal tubular loop and the early distal tubule close to the macula densa. Tubular fluid was collected close to the macula densa to determine the tubuloglomerular feedback signal ([Na-Cl-K]_MD) and single nephron glomerular filtration rate (SNGFR; by inulin clearance). Bowman space was punctured to determine the hydrostatic pressure (P_Bow). Measurements were performed under control conditions and following application of the SGLT2/SGLT1 inhibitor phlorizin into the early proximal tubule, i.e., without changing systemic blood glucose levels. Basal measurements (con) revealed that glomerular hyperfiltration in diabetes was associated with reductions in [Na-Cl-K]_MD and P_Bow. Adding phlorizin (P) had a small effect in non-diabetic rats, but normalized [Na-Cl-K]_MD, P_Bow, and SNGFR in diabetes. c Kidneys are programmed to retain glucose. As a consequence, diabetes induces a primary hyperreabsorption in proximal tubules involving enhanced Na⁺-glucose cotransport and tubular growth. The concomitant enhanced reabsorption of sodium causes glomerular hyperfiltration through tubuloglomerular feedback ([Na-Cl-K]_MD) and reducing tubular back pressure (P_Bow) thereby limiting sodium and volume retention. SGLT2 contributes to the tubular hyperreabsorption, and as a consequence, SGLT2 inhibition mitigates these changes and lowers glomerular hyperfiltration. This figure was modified from [185]

Fig. 8

Tubuloglomerular feedback, SGLT2 inhibition, and SGLT1 as a glucose sensor in the macula densa. The tubuloglomerular feedback (TGF) establishes an inverse relationship between the Na-Cl-K delivery to the macula densa and GFR of the same nephron. (1 + 2) The macula densa senses an increase in luminal Na-Cl-K delivery by a NKCC2-dependent mechanism, which then enhances the basolateral release of ATP. (3) ATP is converted by endonucleotidases CD73/39 to adenosine (ADO). (4) ADO activates the adenosine A₁ receptor in vascular smooth muscle cells (VSMC) of the afferent arteriole to increase cytosolic Ca²⁺ and induce vasoconstriction. (5) ADO can also activate adenosine A₂ receptors on VSMC of the efferent arteriole to reduce cytosolic Ca²⁺ and induce vasodilation. (6) Both effects contribute to the TGF mechanism and lower GFR. (7) Due to upstream tubular hyperreabsorption, diabetes lowers Na-Cl-K delivery to the macula densa. SGLT2 inhibition attenuates the hyperreabsorption, increase Na-Cl-K delivery to the macula densa, and lowers GFR. (8) An increased Na-Cl-K delivery also activates nitric oxide synthase NOS1 in the macula densa. (9) The formed nitric oxide (NO) diffuses across the interstitium and dilates the afferent arteriole, thereby partially offsetting the afferent arteriolar vasoconstrictor tone of TGF. (10) When glucose delivery to the macula densa is increased (by hyperglycemia or SGLT2 inhibition), SGLT1 in the luminal membrane takes up glucose, a process that is linked to the phosphorylation, activation, and increased expression of NOS1 in the macula densa. The resulting NO tone dilates the afferent arteriole and enhances GFR. (11) Volume depletion (e.g., following SGLT2 inhibition) inhibits NOS1 activity. MC, mesangium cell

Fig. 9

Proposed mechanisms of kidney protection by SGLT2 inhibition. SGLT2 inhibition reduces diabetes-induced hyperreabsorption of glucose and Na⁺ in the early proximal tubule. This lowers hyperglycemia and increases NaCl and fluid delivery to the downstream macula densa. The latter reduces glomerular filtration rate (GFR) through the physiology of tubuloglomerular feedback (TGF) (1) and by increasing hydrostatic pressure in Bowman’s space (P_Bow) (2). The TGF effect on GFR includes afferent arteriole constriction and potentially efferent arteriole dilation, which both reduce glomerular capillary pressure (P_GC). Reduction in GFR is the primary mechanism for reducing tubular transport work (3), particularly in the proximal convoluted tubule (PCT), thereby lowering cortical oxygen demand Q_O2 (4) and increasing cortical oxygen tension P_O2 (5). Lowering GFR attenuates tubular growth and albuminuria and consequently kidney inflammation (6). Tubular transport work is further reduced by lowering blood glucose and by cellular SGLT2 blockade itself (7). Less hyperglycemia causes less tubular growth, albuminuria, and inflammation (8). SGLT2 inhibition shifts glucose reabsorption downstream, particularly to the S3 segment where SGLT1 compensates and reduces the risk of hypoglycemia. Shifting glucose and Na⁺ reabsorption to S3 and mTAL segments raises oxygen demand (9) and lowers P_O2 in the outer medulla (OM) (5). On the other hand, lower medullary P_O2 may stimulate pathways induced by hypoxia-inducible factor (HIF), including erythropoietin (EPO) (10), thereby increasing hematocrit (11), which improves O₂ delivery to kidney medulla and cortex (12) and heart O₂ (13). The diuretic and natriuretic effects of SGLT2 inhibition further increase hematocrit (Hct) (14) and reduce circulating volume, blood pressure (15), and body weight, which all can help protect the failing heart. The overall reduced and better distributed renal transport activity increases cortical oxygen availability. This improves the cortical energy balance and tubular integrity, thereby allowing to maintain a higher tubular transport capacity and GFR in the long term (16). UNaV, urinary sodium excretion; UV, urinary flow rate. Adapted from [116]

Fig. 10

The integrated effects of SGLT1 in the diabetic kidney. a Blue arrows indicate positive interactions. Hyperglycemia enhances filtered glucose and induces tubular growth. This increases Na⁺-glucose cotransport, thereby maintaining hyperglycemia and reducing urinary Na⁺ and fluid excretion, with a larger contribution of SGLT2 versus SGLT1. Lesser urinary Na⁺ and fluid excretion increases effective circulating volume (ECV) and blood pressure (BP). Tubular hyperreabsorption lowers tubular backpressure in Bowman space (P_Bow) and the NaCl delivery and concentration at the macula densa (MD), both increasing glomerular filtration rate (GFR) to restore urinary Na⁺ and fluid excretion. An increase in glucose delivery to the MD indicates that upstream Na⁺-glucose cotransport has been saturated. This is sensed by SGLT1 in the MD and, by stimulating MD nitric oxide synthase 1 (NOS1), further increases GFR to compensate for maximized Na⁺-glucose cotransport. At the same time, SGLT1-mediated glucose sensing may trigger tubular growth to enhance the tubular glucose transport capacity. SGLT1 inhibition has a relatively small effect on diabetic tubular hyperreabsorption and thus induces little natriuresis and diuresis. Through inhibition of MD-NOS1 upregulation and lowering of hyperfiltration, however, SGLT1 inhibition induces a relatively larger antinatriuretic and antidiuretic effect. As a consequence, SGLT1 inhibition can increase ECV with the resulting suppression in renin and increase in BP aiming to restore renal Na⁺ and fluid excretion and ECV. Adapted from [161]. b Sensing proximal tubular hyperreabsorption via changes in both NaCl and glucose at the macula densa may allow adaptive increases in GFR over a wider range of filtered glucose. The abscissa refers to filtered glucose