Changes in Proximal Tubular Reabsorption Modulate Microvascular Regulation via the TGF System

Abstract

This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium–glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium–hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.

Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure

“…Last, sodium-hydrogen exchanger 3 inhibition enhances sodium delivery to the macula densa, activating tubuloglomerular feedback and resulting in a decline in glomerular filtration rate. 33,34 We observed a decrease in eGFR during the first 4 weeks of randomized therapy, which was fully reversed during the withdrawal period. Taken collectively, these observations suggest that, during longterm treatment with SGLT2 inhibitors, tolerance does not develop to the effect of these drugs to inhibit SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule.…”

Furosemide attenuates tubulointerstitial injury and allows functional testing of porcine kidneys during normothermic machine perfusion

“…In a normally functioning tubular system, an increased concentration is sensed by the macula densa, which activates the tubuloglomerular feedback (TGF) mechanism and induces vasoconstriction. [37][38][39] However, furosemide also inhibits the NKCC2 cotransporters of the macula densa, which impairs their sensory function. This deactivates the TGF system, resulting in vasodilatation and increased renal blood flow.…”

“…Furosemide reduces the reabsorption of sodium and chloride, which increases the intratubular concentration of these electrolytes. In a normally functioning tubular system, an increased concentration is sensed by the macula densa, which activates the tubuloglomerular feedback (TGF) mechanism and induces vasoconstriction 37–39 . However, furosemide also inhibits the NKCC2 cotransporters of the macula densa, which impairs their sensory function.…”

Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis

“…Despite GTB, the delivery of Na + to the tubular segments beyond the proximal tubule and/or loop of Henle will increase whenever GFR increases or whenever a primary impairment of proximal Na + reabsorption occurs due to transporter malfunction or dysregulation [ 28 , 31 ]. The amount of Na + escaping the reabsorption in the proximal nephron is sensed by macula densa in the juxtaglomerular apparatus and sets the afferent arteriole tone, the mechanism of which is referred to as TGF [ 30 ].…”