Tubule-vascular feedback in renal autoregulation

Abstract

Afferent arteriole (Af-Art) diameter regulates pressure and flow into the glomerulus, which are the main determinants of the glomerular filtration rate. Thus, Af-Art resistance is crucial for Na⁺ filtration. Af-Arts play a role as integrative centers, where systemic and local systems interact to determine the final degree of resistance. The tubule of a single nephron contacts an Af-Art of the same nephron at two locations: in the transition of the thick ascending limb to the distal tubule (macula densa) and again in the connecting tubule. These two sites are the anatomic basis of two intrinsic feedback mechanisms: tubule-glomerular feedback and connecting tubule-glomerular feedback. The cross communications between the tubules and Af-Arts integrate tubular Na⁺ and water processing with the hemodynamic conditions of the kidneys. Tubule-glomerular feedback provides negative feedback that tends to avoid salt loss, and connecting tubule-glomerular feedback provides positive feedback that favors salt excretion by modulating tubule-glomerular feedback (resetting it) and increasing glomerular filtration rate. These feedback mechanisms are also exposed to systemic modulators (hormones and the nervous system); however, they can work in isolated kidneys or nephrons. The exaggerated activation or absence of any of these mechanisms may lead to disequilibrium in salt and water homeostasis, especially in extreme conditions (e.g., high-salt diet/low-salt diet) and may be part of the pathogenesis of some diseases. In this review, we focus on molecular signaling, feedback interactions, and the physiological roles of these two feedback mechanisms.

Keywords: connecting tubule-glomerular feedback; epithelial sodium channel; macula densa; renal autoregulation; sodium-potassium-two chloride cotransporter; tubule-glomerular feedback.

Fig. 1.

A: schematic representation of a nephron and tubular segments. In the transition from the thick ascending limb of the loop of Henle to the distal convoluted tubule (DCT), the afferent arteriole (Af-Art) contacts the macula densa (MD) region and then contacts the connecting tubules (CNTs). The dashed line represents the region shown by the microphotograph. B: interactions of the Af-Art (A) with the MD and CNT (D). The dark brown signal indicates kallikrein-positive cells, a marker of CNTs. The black staining in A and E corresponds to renin-positive cells (juxtaglomerular cells). Ef-Art, efferent arteriole; PT, proximal tubule; G, glomerulus. *Thick ascending loop. [Image used with permission from Barajas et al. (36).]

Fig. 2.

High Na⁺ in the connecting tubules (CNTs) induces afferent arteriole (Af-Art) vasodilation mediated by PGE₂ and epoxyeicosatrienoic acids in a cross-talk mechanism called connecting tubule-glomerular feedback (CTGF). A: schematic representation of the microperfusion system (in vitro), where an Af-Art and the attached CNT were perfused simultaneously and the diameter of the Af-Art was video recorded. B: changes in Af-Art diameter when the Af-Art was preconstricted with norepinephrine (NE) and the attached CNT was then exposed to different Na⁺ concentrations. The high Na⁺ concentration induced vasodilation that was reversible when the Na⁺ level was decreased. C: effect of the epithelial Na⁺ channel blocker amiloride in preventing the vasodilation induced by high Na⁺ levels in the CNT. D: additive inhibitory effects of the epoxygenase inhibitor ONO-AE3-208 and PGE₂ type 4 receptor (EP4) blocker MS-PPOH on CTGF. Ef-Art, efferent arteriole; GL, glomerulus. *P < 0.05; ***P < 0.001. [Images modified with permission from Ren et al. (35, 38).]

Fig. 3.

Single nephron micropuncture technique. A: schematic showing how one micropipette is inserted in the early proximal tubule and the tubular flow is stopped by a grease block (GB). That pipette, proximal to the GB, is used to measure stop-flow pressure (P_SF) as a surrogate for glomerular pressure. Thus, the changes observed in the glomerulus are transmitted to the proximal tubule. A second pipette (perfusion pipette) is inserted distal to the GB. The perfusion pipette is used to infuse NaCl at different rates with ion transport inhibitors to evaluate tubule-glomerular feedback and connecting tubule-glomerular feedback. The perfusate reached the macula densa and distal nephron, including the connecting tubule (CNT). B: classical P_SF curve when the perfusion rate of NaCl solution is increased (open circle) and the exaggerated vasoconstriction and decrease in P_SF (close circle) when an epithelial Na⁺ channel inhibitor (benzamil) is added to the solution. ***P < 0.001. Af-Art, afferent arteriole; Ef-Art, efferent arteriole; DCT, distal convoluted tubule.

Fig. 4.

Stop-flow pressure (P_SF) changes in response to different Na⁺ transporter inhibitors. A: normal vasoconstriction response and its reproducibility in time (second curve, time control). B: blunted vasoconstriction that occurred when furosemide (Furo; Na⁺-K⁺-2Cl⁻ cotransporter inhibitor) was included in the tubular fluid. C: however, when the combination of furosemide plus benzamil [Benz; an epithelial Na⁺ channel and, therefore, connecting tubule-glomerular feedback (CTGF) blocker] was added to the perfusion, a new vasoconstricting, tubule-glomerular feedback (TGF)-like response was observed. D: TGF-like response was due to the activation of Na⁺/H⁺ exchanger 2 channels in the macula densa, as demonstrated by the fact that the combined use of the Na⁺/H⁺ exchanger inhibitor dimethyl-amiloride (DMA) decreased the TGF-like response. E: vasodilation observed when both TGF and the TGF-like response were inhibited. F: the vasodilator response was due to CTGF, as shown by the fact that vasodilation was completely inhibited by adding benzamil to the perfusate. *P < 0.05; **P < 0.01; ***P < 0.001. [Modified from Wang et al. (9).]

Fig. 5.

Stop-flow pressure (P_SF) after unilateral nephrectomy (Unx). A: after Unx, there was a blunted vasoconstriction response when tubular Na⁺ levels were increased by increasing the perfusion rate (open circles). At least part of the blunted vasoconstriction was due to highly activated connecting tubule-glomerular feedback (CTGF), as shown by the fact that inhibition with the epithelial Na⁺ channel blocker benzamil restored the vasoconstriction response. B: quantitative analysis of CTGF in sham- or vehicle-treated animals. *P < 0.005. [Modified with permission from Monu et al. (4).]