Figure 1.

Postulated mechanisms in normal physiology and hyperfiltration in early stages of nephropathy and after combined inhibition of SGLT2 and RAAS. A, Under physiologic conditions, tubuloglomerular feedback (TGF) signaling maintains stable glomerular filtration rate (GFR) by modulation of preglomerular arteriole tone. In cases of conditional increases in GFR, the macula densa within the juxtaglomerular apparatus senses an increase in distal tubular sodium delivery and adjusts GFR through TGF accordingly. Neurohormonal signaling using the renin-angiotensin-aldosterone system (RAAS) contributes to maintenance of stable GFR by modulating postglomerular arteriole tone. B, Under chronic hyperglycemic conditions during diabetes, increased proximal sodium-glucose cotransporter 2 (SGLT2)–mediated reabsorption of sodium (Na⁺) and glucose impairs this feedback mechanism. Thus, despite increased GFR, the macula densa is exposed to lowered sodium concentrations and results in dilation of the afferent intrarenal arteriole. Increased activation of the renin-angiotensin-aldosterone neurohormonal system in diabetes causes constriction at the efferent intrarenal arteriole. Together, impairment of TGF and neurohormonal signaling likely leads to inadequate arteriole tone at the afferent and efferent arterioles and renal perfusion is increased. C, SGLT2 inhibition with empagliflozin treatment blocks proximal tubule glucose and sodium reabsorption, which leads to increased sodium delivery to the macula densa. This condition restores TGF by means of appropriate modulation of arteriolar tone (e.g., afferent vasoconstriction). Blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor, ramipril, leads to efferent vasodilation. The overall effect of afferent vasocontraction with SGLT2 inhibition and efferent vasodilation with ACE inhibition reduces renal plasma flow and hyperfiltration. Modified from Cherney et al.¹⁶