A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback

Abstract

Purpose of review: In this review, we summarized the current knowledge of connecting tubule-glomerular feedback (CTGF), a novel mechanism of renal microcirculation regulation that integrates sodium handling in the connecting tubule (CNT) with kidney hemodynamics.

Recent findings: Connecting tubule-glomerular feedback is a crosstalk communication between the CNT and the afferent arteriole (Af-Art), initiated by sodium chloride through the epithelial sodium channel (ENaC). High sodium in the CNT induces Af-Art vasodilation, increasing glomerular pressure and the glomerular filtration rate and favoring sodium excretion. CTGF antagonized and reset tubuloglomerular feedback and thus increased sodium excretion. CTGF is absent in spontaneous hypertensive rats and is overactivated in Dahl salt-sensitive rats. CTGF is also modulated by angiotensin II and aldosterone. CTGF is a feedback mechanism that integrates sodium handling in the CNT with glomerular hemodynamics. Lack of CTGF could promote hypertension, and CTGF overactivation may favor glomerular damage and proteinuria. More studies are needed to explore the alterations in renal microcirculation and the role of these alterations in the genesis of hypertension and glomerular damage in animals and humans.

Key points: • CTGF is a vasodilator mechanism that regulates afferent arteriole resistance. • CTGF is absent in spontaneous hypertensive rats and overactivated in Dahl salt-sensitive rats. • CTGF in excess may promote glomerular damage and proteinuria, while the absence may participate in sodium retention and hypertension.

Keywords: Connecting tubule-glomerular feedback; ENaC; Hypertension; Proteinuria; Tubuloglomerular feedback.

Fig. 1

Interaction between tubules and arterioles in the nephron. The tubule gets contact with afferent arteriole (AF-Art) at least in two sites: at the juxtaglomerular apparatus (JGA) (dashed line box) where the macula densa (MD) interact with the Af-Art. The JGA is the site for the tubule-glomerular feedback (TGF). The second contact between tubules and Af-Art occurs at the connecting tubule (CNT); there is the anatomical site of the connecting tubule-glomerular feedback (CTGF) (dark box). Ef-Art efferent arteriole, DCT distal convoluted tubule, CCD cortical collecting ducts

Fig. 2

Schematic representation of tubuloglomerular feedback (TGF) and connecting tubule-glomerular feedback (CTGF). TGF occurs at the macula densa when sodium chloride is detected through the sodium-potassium-two chloride cotransporter (NKCC2) and secondary to the sodium proton exchanger (NHE). TGF is mediated by adenosine triphosphate and/or adenosine inducing the afferent arteriole (Af-Art) vasoconstriction. CTGF occurs at the connecting tubule by the epithelial sodium channel (ENaC) which detects the distal sodium load. Prostaglandins E2 (PPGE2) and epoxyeicosatrienoic acids (EETs) are released and induce the Af-Art vasodilation. CTGF participates in the TGF resetting, where the sodium load must be higher to induce the same vasoconstriction, due to the vasodilation induced by CTGF

Fig. 3

Alteration of the TGF-CTGF equilibrium. a Data suggest that if the TGF response is exaggerated, the kidney will increase sodium retention by decreasing the glomerular filtration (GFR) and activating the renin-angiotensin system. These changes would increase the blood pressure (BP) that finally will increase GFR restoring the sodium filtration but a new homeostatic BP level. At the same time, the glomerulus will be more protected to barotrauma due to the Af-Art vasoconstriction. b Contrarily, an excess of CTGF will allow the transmission of systemic BP to the glomerulus, favoring the barotrauma in the presence of systemic hypertension. At the same time, the exaggerated CTGF will induce a high GFR (hyperfiltration) that will favor sodium excretion, ameliorating the increase in BP. TGF tubule glomerular feedback, CTGF connecting tubule-glomerular feedback, Af-Art afferent arteriole

Fig. 4

Effects of amiloride in the kidneys. Amiloride is an epithelial sodium channel (ENaC) inhibitor, used as a potassium sparing diuretic in the clinic. Amiloride, by inhibiting ENaC, decrease sodium retention and connecting tubule-glomerular feedback (CTGF). Despite the direct ENaC effects, amiloride inhibits the urokinase-type plasminogen activator (uPA) and its receptor uPAR. uPA converts plasminogen in plasmin, a serine protease that can cleave the gamma sub-unit of ENaC increasing the ENaC activity. uPA can act directly or by attaching to the uPAR that will allow a more physically limited activity of uPA. uPAR also have effects independent of uPA, such as podocyte activation and inflammation. Amiloride also is an uPAR blocker