SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for kidney failure and are a key component of guideline-directed therapy for CKD. While SGLT2 inhibitors' ability to activate tubuloglomerular feedback and reduce hyperfiltration-mediated kidney injury is considered to be the central mechanism for kidney protection, recent data from experimental studies raise questions on the primacy of this mechanism. This review examines SGLT2 inhibitors' role in tubuloglomerular feedback and summarizes emerging evidence on following of SGLT2 inhibitors' other putative mechanisms for kidney protection: optimization of kidney's energy substrate utilization and delivery, regulation of autophagy and maintenance of cellular homeostasis, attenuation of sympathetic hyperactivity, and improvement in vascular health and microvascular function. It is imperative to examine the effect of SGLT2 inhibition on these different physiologic processes to help our understanding of mechanisms underpinning kidney protection with this important class of drugs.

Figure 1

SGLT2 inhibitors and TGF. Chronic hyperglycemia increases SGLT2 expression in PCTs leading to enhanced proximal reabsorption of sodium (Na) and glucose and blunting of TGF. SGLT2 inhibitors block Na and glucose reabsorption in PCT, increase Na and glucose in macula densa, activate TGF, decrease intraglomerular pressure, and reduce hyperfiltration-mediated progressive kidney injury.^, PCT, proximal convoluted tubule; SGLT2, sodium-glucose cotransporter 2; TGF, tubuloglomerular feedback.

Figure 2

Salt intake, protein intake, and medication SGLT2 inhibitor's effect on TGF. SGLT2 inhibitors may activate TGF mechanism.^, High salt intake, high protein intake, and furosemide may blunt SGLT2 inhibitor's effects on TGF.^–,, Low salt intake, low protein intake, and RAAS inhibitors may potentiate SGLT2 inhibitor's effects on TGF. RAAS, renin-angiotensin-aldosterone.

Figure 3

SGLT2 inhibitors and ketogenesis. SGLT2 inhibitors increase glycosuria, lower blood glucose, and create a negative energy balance. These mechanisms stimulate hepatic ketogenesis by promoting lipolysis, lowering pancreatic insulin secretion, and increasing pancreatic glucagon secretion.^,

Figure 4

SGLT 2 inhibitors and tissue oxygenation. SGLT2 inhibitors improve tissue oxygenation in kidneys by decreasing proximal tubular oxygen (O₂) usage. SGLT2 inhibitors potentially increase O₂ delivery through erythropoietin-mediated increase in hematocrit, angiogenesis, and mitochondrial function. Improvement in tissue oxygenation lowers hypoxia-associated kidney damage.^–

Figure 5

SGLT 2 inhibitors and autophagy. SGLT2 inhibitors create negative energy balance which stimulates nutrient deprivation sensors in tissues. Tissues respond to nutrient deficiency by inducing pathways that inhibit mTORC1 and stimulate AMPK and SIRT1.^– SIRT1 stimulates AMPK and HIF-2α and suppresses HIF-1α.^,, These pathways ultimately contribute to the reduction in kidney damage by improving autophagy and lowering inflammation and fibrosis. AMPK, 5′adenosine monophosphate-activated protein kinase; HIF, hypoxia-inducible factor; mTORC1, mammalian target of rapamycin protein complex 1; SIRT1, sirtuin 1.

Figure 6

CKD, SGLT2 inhibitors, and sympathetic tone. There is an increase in sympatho-excitatory afferent signals from damaged kidneys to the brain in CKD.^, This leads to an increase in central sympathetic outflow. Increased sympathetic outflow increases heart rate and BP, contributes to LVH and CVDs, increases SGLT2 expression in the PCT, activates NH1 and NH3, increases sodium retention, increases oxidative stress, contributes to arterial stiffness, and worsens endothelial function.^– SGLT2 inhibitors mitigate these adverse effects of increased sympathetic tone by promoting natriuresis, lowering BP, inhibiting NH3 activity, improving arterial function, and improving endothelial function.^,– CVD, cardiovascular disease; LVH, left ventricular hypertrophy; NH1, Na⁺/H⁺ exchanger isoform 1; NH3, Na⁺/H⁺ exchanger isoform 3.