Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors (original) (raw)
The concept of using sodium-glucose cotransporter-2 (SGLT2) inhibitors for treatment of kidney disease has been a story of remarkable serendipity. In a sense, it has been a story line of science in reverse — clinical observations driving preclinical research — a turnaround for the usual order of inquiry for unraveling potential therapeutic mechanisms. The concept of inhibiting SGLTs in the kidney tubules to induce glucosuria, and thereby lower blood glucose and correct insulin resistance, was introduced by Rossetti, DeFronzo, and colleagues in a seminal study of diabetic rats published in the JCI in 1987 (1). They studied an oral agent, phlorizin, but it was not feasible for clinical translation because of breakdown in the gastrointestinal tract and inhibition of gut SGLT1, leading to diarrhea. Cloning and characterization of SGLTs in the human body soon followed (2, 3). SGLT2 was found on the luminal side of proximal tubule epithelial cells (Figure 1A) and not elsewhere, which made this receptor an ideal target for pharmacologic inhibition (3, 4). Glucose reabsorption has high energy requirements due to coupling of ATPase with sodium reabsorption (4). Glucose moves across a concentration gradient in proximal tubular epithelial cells into the blood by facilitated transport via glucose transporter 2 (GLUT2) on the basolateral side. SGLT2 inhibitors with proven benefit for kidney protection (canagliflozin, dapagliflozin, and empagliflozin) are aryl-C-glucosides that are not cleaved in the gut with high selectivity for SGLT2 over SGLT1 (5–7). Notably, about 90% of the filtered glucose load is reabsorbed in the proximal tubular S1 and S2 segments (4). Although SGLT2 inhibitors block glucose reabsorption in the S1 and S2 segments, increased glucose reuptake by SGLT1 in the proximal tubular S3 segment results in a net inhibitory effect of about 50% of the filtered glucose load.
SGLT2 inhibitors mediate kidney-protective effects via receptor- and non-receptor-mediated pathways. (A) SGLT2 inhibitors regulate inflammation and glycolysis through SGLT2 receptors. The binding of an SGLT2 inhibitor to the SGLT2 receptor blocks glucose reabsorption from the luminal side of proximal tubular epithelial cells in the kidney, leading to low intracellular glucose, and consequently, less glucose transport across the basolateral side into the blood by GLUT2 (4). Reduced sodium reabsorption at this site also lessens ATPase activity and the conversion of ATP to ADP, which generates energy for solute transport. Further, low intracellular glucose activates AMPK, which phosphorylates regulatory proteins that inhibit mTORC1 signaling (21). Importantly, suppression of mTORC1 may block stimulatory actions to promote expression of inflammatory mediators and glycolysis at this site. (B) SGLT2 inhibitors may also modulate inflammation, intracellular glucose levels, and EPO production through non-receptor-mediated pathways. In a variety of cells from the kidney (e.g., proximal tubular epithelial cells, podocytes, fibroblasts) and the cardiovascular system (e.g., cardiac myocytes, endothelial cells), SGLT2 inhibitors may have off-target effects. SGLT2 inhibitors can putatively bind mTORC1 intracellularly to inhibit expression of inflammatory mediators and/or glycolysis depending on cell type (19). Cardiac myocytes contain GLUT1 and GLUT4 that can be blocked by intracellular interaction with SGLT2 inhibitors and, consequently, lower glucose transfer into the cell along with AMPK activation that may also inhibit mTORC1 (20). Conversely, SGLT2 inhibitors can dock with SIRT1 and increase its activity to oppose expression of inflammatory mediators (22, 23). In kidney medullary interstitial fibroblasts, SIRT1 and hypoxia could activate HIF-2α and thereby increase EPO production (25).
As drug development moved forward for hyperglycemia, cardiovascular outcomes trials (CVOTs) for safety after regulatory approval of glucose-lowering agents were required by the US Food and Drug Administration starting in 2008 (8). The EMPA-REG OUTCOME trial was the first CVOT to demonstrate efficacy as well as safety of an SGLT2 inhibitor for major adverse cardiovascular events in type 2 diabetes. It was also the first to show benefits of a glucose-lowering agent for protection against a range of secondary kidney disease end points: albuminuria onset or progression to macroalbuminuria, doubling of serum creatinine with estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2, kidney failure, and death due to kidney disease (9). Similar results on secondary kidney disease end points were subsequently demonstrated with canagliflozin, dapagliflozin, and ertugliflozin in their respective CVOTs (10–12). These benefits were verified by a trilogy of trials with kidney disease end points as the primary outcomes: CREDENCE, DAPA-CKD, and EMPA-KIDNEY (5–7). Together, these trials, meta-analyzed with the CVOTs and heart failure trials, found clear superiority of SGLT2 inhibitors compared with placebo, with a relative risk reduction of 40% for kidney disease progression in patients with or without type 2 diabetes (13).