Glomerulotubular Balance Research Articles

Regulation of Glomerulotubular Balance IV: Implication of Aquaporin 1 in Flow-Dependent Proximal Tubule Transport and Cell Volume

Regulation of Glomerulotubular Balance IV: Implication of Aquaporin 1 in Flow-Dependent Proximal Tubule Transport and Cell Volume

The Benefit of Sodium-Glucose Co-Transporter Inhibition in Heart Failure: The Role of the Kidney.

In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na+ and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na+ concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O2 consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na+ coupled with glucose and can restore renal O2 demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes.

Regulation of glomerulotubular balance. IV. Implication of aquaporin 1 in flow-dependent proximal tubule transport and cell volume.

The water channel aquaporin-1 (AQP1) is the principal water pathway for isotonic water reabsorption in the kidney proximal tubule (PT). We investigated flow-mediated fluid (Jv) and [Formula: see text] ([Formula: see text]) reabsorption in PTs of the mouse kidney by microperfusion in wild-type (WT) and AQP1 knockout (KO) mice. Experiments were simulated in an adaptation of a mathematical model of the rat PT. An increase in perfusion rate from 5 to 20 nL/min increased Jv and [Formula: see text] in PTs of WT mice. AQP1 KO mice significantly decreased Jv at low and high flow rates compared with control. In contrast, [Formula: see text] was not reduced at either low or high flow rates. Cell volume showed no significant difference between WT and AQP1 KO mice. Renal clearance experiments showed significantly higher urine flow in AQP1 KO mice, but there was no significant difference in either Na+ and K+ or [Formula: see text] excretion. Acid-base parameters of blood pH, Pco2, [Formula: see text], and urine pH were the same in both WT and KO mice. In model calculations, tubules whose tight junction (TJ) water permeability (Pf) was that assigned to the rat TJ, showed no difference in Jv between WT and KO, whereas TJ Pf set to 25% of the rat predicted Jv concordant with our observations from AQP1 KO. These results affirm the dominance of AQP1 in mediating isotonic water reabsorption by the mouse PT and demonstrate that flow-stimulated [Formula: see text] reabsorption is intact and independent of AQP1. With reference to the model, the findings also suggest that TJ water flux in the PT is less prominent in the mouse than in the rat kidney.NEW & NOTEWORTHY We found an absence of flow-dependent modulation of fluid absorption but no effect on either proximal tubule (PT) [Formula: see text] absorption or acid-base parameters in the aquaporin 1 (AQP1) knockout mouse. We affirmed the dominance of the water channel AQP1 in mediating isotonic water reabsorption by the mouse PT and demonstrated that flow-stimulated [Formula: see text] reabsorption is independent of AQP1. With reference to the model, the findings also suggest that tight junctional water flux in the PT is less prominent in the mouse than rat kidney.

Mitochondria in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in the USA. The pathogenesis of DKD is multifactorial and involves activation of multiple signaling pathways with merging outcomes including thickening of the basement membrane, podocyte loss, mesangial expansion, tubular atrophy, and interstitial inflammation and fibrosis. The glomerulo-tubular balance and tubule-glomerular feedback support an increased glomerular filtration and tubular reabsorption, with the latter relying heavily on ATP and increasing the energy demand. There is evidence that alterations in mitochondrial bioenergetics in kidney cells lead to these pathologic changes and contribute to the progression of DKD towards ESRD. This review will focus on the dialogue between alterations in bioenergetics in glomerular and tubular cells and its role in the development of DKD. Alterations in energy substrate selection, electron transport chain, ATP generation, oxidative stress, redox status, protein posttranslational modifications, mitochondrial dynamics, and quality control will be discussed. Understanding the role of bioenergetics in the progression of diabetic DKD may provide novel therapeutic approaches to delay its progression to ESRD.

Restoration of proximal tubule flow-activated transport prevents cyst growth in polycystic kidney disease.

Flow-activated Na+ and HCO3– transport in kidney proximal tubules (PT) underlies relatively constant fractional reabsorption during changes in glomerular filtration rate (GFR) or glomerulotubular balance (GTB). In view of hypothesized connections of epithelial cilia to flow sensing, we examined flow-activated transport in 3 polycystic kidney disease–related mouse models based on inducible conditional KO of Pkd1, Pkd2, and Kif3a. PTs were harvested from mice after gene inactivation but prior to cyst formation, and flow-mediated PT transport was measured. We confirm that higher flow increased both Na+ and HCO3– absorption in control mice, and we observed that this flow effect was preserved in PTs of Pkd1–/– and Kif3a–/–mice. However, flow activation was absent in Pkd2+/– and Pkd2–/– PT. In heterozygous (Pkd2+/–) mice, a dopamine receptor 1 (DA1) antagonist (SCH23390) restored transport flow sensitivity. When given chronically, this same antagonist reduced renal cyst formation in Pkd2–/–, as evidenced by reduced kidney weight, BUN, and the cystic index, when compared with untreated mice. In contrast, SCH23390 did not prevent cyst formation in Pkd1–/– mice. These results indicate that Pkd2 is necessary for normal GTB and that restoration of flow-activated transport by DA1 antagonist can slow renal cyst formation in Pkd2–/– mice.

Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease.

In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self‐regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.

Abstract 058: High Sodium Intake Induces a Catabolic State via Glomerular Hyperfiltration and Enhanced Glomerulotubular Balance in Essential Hypertension

Background: A metabolic shift in energy expenditure toward a catabolic state upon high sodium (Na + ) diet, ultimately favouring endogenous water accrual and body fluid preservation, has recently been described in a rodent model. Objective: To investigate the impact of high Na + intake on renal Na + /water handling and metabolic signatures in a large real-life cohort of patients. Methods and Results: We analysed biochemical data from 767 hypertensive patients (429 males, 55.9%; age 47 ± 13 years; BMI 25.6 [23.0-29.0] kg/m 2 ) in washout from drugs affecting the renin-angiotensin-aldosterone system at the time of screening for secondary causes and with a conclusive diagnosis of essential hypertension (2012-2017). Classes of Na + intake ( L ow ≤2.3g/d; M edium 2.3-5g/d; H igh >5g/d) were defined based on urinary 24h Na + excretion (uNaV). The fractional excretion (FE) of Na + increased with increasing Na + intake (L: 0.39% [0.30-0.47] vs H: 0.81% [0.73-0.98], p < 0.001), while FE of free water decreased (L: 1.13% [0.73-1.72] vs H: 0.89% [0.69-1.12], p = 0.015). uNaV was an independent predictor of glomerular filtration rate (GFR, estimated by creatinine clearance; H: 130 ± 33 vs M: 111 ± 52 and L: 96 ± 39 ml/min/1.73m 2 ; p < 0.001 for comparisons) after correction for age, sex, BMI, renin, aldosterone and uKV (p = 0.001). This resulted in a marked increase in the 24h tubular Na + reabsorption and, accordingly, in the estimated energy expenditure (Δ H vs L= 18 [12-24] kcal/d, p < 0.001). At non-targeted LC/MS metabolomics (n = 67), metabolites increased (p < 0.05) in H vs L Na + intake mostly entailed intermediates or end products of the urea cycle and products of protein catabolism. Urinary 24h cortisol excretion, as a potential determinant of catabolism, increased with Na + intake (n = 137; L: 63 [36-72] nmol, M: 60 [47-86] nmol, H: 86 [75-139] nmol; p < 0.001), but its strongest predictor at multivariate regression analysis was GFR (p = 0.001). Conclusions: Kidneys can effectively dissociate Na + and water handling upon high Na + diet, at the cost of glomerular hyperfiltration, enhanced glomerulotubular balance, increased tubular energy expenditure and, ultimately, protein catabolism from endogenous or excess exogenous sources. This has broad implications on global cardiovascular risk.

A computational model of epithelial solute and water transport along a human nephron.

We have developed the first computational model of solute and water transport from Bowman space to the papillary tip of the nephron of a human kidney. The nephron is represented as a tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type. The model is formulated for steady state, and consists of a large system of coupled ordinary differential equations and algebraic equations. Model solution describes luminal fluid flow, hydrostatic pressure, luminal fluid solute concentrations, cytosolic solute concentrations, epithelial membrane potential, and transcellular and paracellular fluxes. We found that if we assume that the transporter density and permeabilities are taken to be the same between the human and rat nephrons (with the exception of a glucose transporter along the proximal tubule and the H+-pump along the collecting duct), the model yields segmental deliveries and urinary excretion of volume and key solutes that are consistent with human data. The model predicted that the human nephron exhibits glomerulotubular balance, such that proximal tubular Na+ reabsorption varies proportionally to the single-nephron glomerular filtration rate. To simulate the action of a novel diabetic treatment, we inhibited the Na+-glucose cotransporter 2 (SGLT2) along the proximal convoluted tubule. Simulation results predicted that the segment’s Na+ reabsorption decreased significantly, resulting in natriuresis and osmotic diuresis.

Cdc42 activation couples fluid shear stress to apical endocytosis in proximal tubule cells.

Cells lining the kidney proximal tubule (PT) respond to acute changes in glomerular filtration rate and the accompanying fluid shear stress (FSS) to regulate reabsorption of ions, glucose, and other filtered molecules and maintain glomerulotubular balance. Recently, we discovered that exposure of PT cells to FSS also stimulates an increase in apical endocytic capacity (Raghavan et al. PNAS, 111:8506–8511, 2014). We found that FSS triggered an increase in intracellular Ca2+ concentration ([Ca2+]i) that required release of extracellular ATP and the presence of primary cilia. In this study, we elucidate steps downstream of the increase in [Ca2+]i that link FSS‐induced calcium increase to increased apical endocytic capacity. Using an intramolecular FRET probe, we show that activation of Cdc42 is a necessary step in the FSS‐stimulated apical endocytosis cascade. Cdc42 activation requires the primary cilia and the FSS‐mediated increase in [Ca2+]i. Moreover, Cdc42 activity and FSS‐stimulated endocytosis are coordinately modulated by activators and inhibitors of calmodulin. Together, these data suggest a mechanism by which PT cell exposure to FSS is translated into enhanced endocytic uptake of filtered molecules.

Proximal tubule apical endocytosis is modulated by fluid shear stress via an mTOR-dependent pathway.

Cells lining the proximal tubule (PT) have unique membrane specializations that are required to maintain the high-capacity ion transport and endocytic functions of this nephron segment. PT cells in vivo acutely regulate ion transport in response to changes in glomerular filtration rate (GFR) to maintain glomerulotubular balance. PT cells in culture up-regulate endocytic capacity in response to acute changes in fluid shear stress (FSS); however, it is not known whether GFR modulates PT endocytosis to enable maximally efficient uptake of filtered proteins in vivo. Here, we show that cells cultured under continuous FSS develop an expanded apical endocytic pathway and increased endocytic capacity and lysosomal biogenesis. Furthermore, endocytic capacity in fully differentiated cells is rapidly modulated by changes in FSS. PT cells exposed to continuous FSS also acquired an extensive brush border and basolateral membrane invaginations resembling those observed in vivo. Culture under suboptimal levels of FSS led to intermediate phenotypes, suggesting a threshold effect. Cells exposed to FSS expressed higher levels of key proteins necessary for PT function, including ion transporters, receptors, and membrane-trafficking machinery, and increased adenine nucleotide levels. Inhibition of the mechanistic target of rapamycin (mTOR) using rapamycin prevented the increase in cellular energy levels, lysosomal biogenesis, and endocytic uptake, suggesting that these represent a coordinated differentiation program. In contrast, rapamycin did not prevent the FSS-induced increase in Na+/K+-ATPase levels. Our data suggest that rapid tuning of the endocytic response by changes in FSS may contribute to glomerulotubular balance in vivo. Moreover, FSS provides an essential stimulus in the differentiation of PT cells via separate pathways that up-regulate endocytosis and ion transport capacity. Variations in FSS may also contribute to the maturation of PT cells during kidney development and during repair after kidney injury.

Regulation of glomerulotubular balance: flow-activated proximal tubule function.

The purpose of this review is to summarize our knowledge and understanding of the physiological importance and the mechanisms underlying flow-activated proximal tubule transport. Since the earliest micropuncture studies of mammalian proximal tubule, it has been recognized that tubular flow is an important regulator of sodium, potassium, and acid-base transport in the kidney. Increased fluid flow stimulates Na+ and HCO3- absorption in the proximal tubule via stimulation of Na/H-exchanger isoform 3 (NHE3) and H+-ATPase. In the proximal tubule, brush border microvilli are the major flow sensors, which experience changes in hydrodynamic drag and bending moment as luminal flow velocity changes and which transmit the force of altered flow to cytoskeletal structures within the cell. The signal to NHE3 depends upon the integrity of the actin cytoskeleton; the signal to the H+-ATPase depends upon microtubules. We have demonstrated that alterations in fluid drag impact tubule function by modulating ion transporter availability within the brush border membrane of the proximal tubule. Beyond that, there is evidence that transporter activity within the peritubular membrane is also modulated by luminal flow. Secondary messengers that regulate the flow-mediated tubule function have also been delineated. Dopamine blunts the responsiveness of proximal tubule transporters to changes in luminal flow velocity, while a DA1 antagonist increases flow sensitivity of solute reabsorption. IP3 receptor-mediated intracellular Ca2+ signaling is critical to transduction of microvillus drag. In this review, we summarize our findings of the regulatory mechanism of flow-mediated Na+ and HCO3- transport in the proximal tubule and review available information about flow sensing and regulatory mechanism of glomerulotubular balance.

Students′ convoluted trouble with renal autoregulation: A teaching note for students and physiology educators

This teaching insight focused on the common misperceptions regarding renal autoregulation (RenAutoreg). The classical model of RenAutoreg is an intrinsic mechanism of a denervated kidney in an in vitro setup. The whole body homeostatic in vivo model of RenAutoreg in a few major texts accounts for the confusion in understanding the intrinsic nature of RenAutoreg first defined originally. RenAutoreg correctly distinguished will provide the basis for appreciating the other intrinsic renal mechanism called glomerulo-tubular balance and also the second fiddle role of RenAutoreg in the homeostasis of extracellular fluid/blood volume and arterial pressure.

Discerning the role of mechanosensors in regulating proximal tubule function.

All cells in the body experience external mechanical forces such as shear stress and stretch. These forces are sensed by specialized structures in the cell known as mechanosensors. Cells lining the proximal tubule (PT) of the kidney are continuously exposed to variations in flow rates of the glomerular ultrafiltrate, which manifest as changes in axial shear stress and radial stretch. Studies suggest that these cells respond acutely to variations in flow by modulating their ion transport and endocytic functions to maintain glomerulotubular balance. Conceptually, changes in the axial shear stress in the PT could be sensed by three known structures, namely, the microvilli, the glycocalyx, and primary cilia. The orthogonal component of the force produced by flow exhibits as radial stretch and can cause expansion of the tubule. Forces of stretch are transduced by integrins, by stretch-activated channels, and by cell-cell contacts. This review summarizes our current understanding of flow sensing in PT epithelia, discusses challenges in dissecting the role of individual flow sensors in the mechanosensitive responses, and identifies potential areas of opportunity for new study.

Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport.

In the proximal tubule, axial flow (drag on brush-border microvilli) stimulates Na(+) and HCO3 (-) reabsorption by modulating both Na/H exchanger 3 (NHE3) and H-ATPase activity, a process critical to glomerulotubular balance. We have also demonstrated that blocking the angiotensin II receptor decreases baseline transport, but preserves the flow effect; dopamine leaves baseline fluxes intact, but abrogates the flow effect. In the current work, we provide evidence implicating cytosolic calcium in flow-dependent transport. Mouse proximal tubules were microperfused in vitro at perfusion rates of 5 and 20 nl/min, and reabsorption of fluid (Jv) and HCO3 (-) (JHCO3) were measured. We examined the effect of high luminal Ca(2+) (5 mM), 0 mM Ca(2+), the Ca(2+) chelator BAPTA-AM, the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate (2-APB), and the Ca-ATPase inhibitor thapsigargin. In control tubules, increasing perfusion rate from 5 to 20 nl/min increased Jv by 62% and JHCO3 by 104%. With respect to Na(+) reabsorption, high luminal Ca(2+) decreased transport at low flow, but preserved the flow-induced increase; low luminal Ca(2+) had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect; thapsigargin decreased baseline flow, leaving the flow effect intact. With respect to HCO3 (-) reabsorption, high luminal Ca(2+) decreased transport at low flow and mildly diminished the flow-induced increase; low luminal Ca(2+) had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect. These data implicate IP3 receptor-mediated intracellular Ca(2+) signaling as a critical step in transduction of microvillous drag to modulate Na(+) and HCO3 (-) transport.

Integrated control of Na transport along the nephron.

The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine. Although almost every nephron segment participates in the reabsorption of Na in the normal kidney, the proximal segments (from the glomerulus to the macula densa) and the distal segments (past the macula densa) play different roles. The proximal tubule and the thick ascending limb of the loop of Henle interact with the filtration apparatus to deliver Na to the distal nephron at a rather constant rate. This involves regulation of both filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback. The more distal segments, including the distal convoluted tubule (DCT), connecting tubule, and collecting duct, regulate Na reabsorption to match the excretion with dietary intake. The relative amounts of Na reabsorbed in the DCT, which mainly reabsorbs NaCl, and by more downstream segments that exchange Na for K are variable, allowing the simultaneous regulation of both Na and K excretion.

Glucagon-like peptide-1 receptor stimulation increases GFR and suppresses proximal reabsorption in the rat.

The incretin hormone glucagon-like peptide-1 (GLP-1) is released from the gut in response to fat or carbohydrate and contributes to negative feedback control of blood glucose by stimulating insulin secretion, inhibiting glucagon, and slowing gastric emptying. GLP-1 receptors (GLP-1R) are also expressed in the proximal tubule, and possibly elsewhere in the kidney. Presently, we examined the effect of a GLP-1R agonist on single-nephron glomerular filtration rate (GFR; SNGFR), proximal reabsorption (Jprox), tubuloglomerular feedback (TGF) responses, and urine flow rate in hydropenic male Wistar and Wistar-Froemter rats. Micropuncture and whole-kidney data were obtained before and during infusion of the GLP-1 agonist exenatide (1 nmol/h iv). SNGFR and Jprox were measured by late proximal collection at both extremes of TGF activation, which was achieved by perfusing Henle's loop at 0 or 50 nl/min. Primary changes in Jprox were revealed by analysis of covariance for Jprox with SNGFR as a covariate. Effects on TGF activation were determined in a separate set of experiments by comparing early distal and late proximal collections. Exenatide increased SNGFR by 33-50%, suppressed proximal tubular reabsorption by 20-40%, doubled early distal flow rate, and increased urine flow rate sixfold without altering the efficiency of glomerulotubular balance, TGF responsiveness, or the tonic influence of TGF. This implies that exenatide is both a proximal diuretic and a renal vasodilator. Since the natural agonist for the GLP-1R is regulated by intake of fat and carbohydrate, but not by salt or fluid, the control of salt excretion by the GLP-1R system departs from the usual negative-feedback paradigm for regulating salt balance.

Regulation of glomerulotubular balance. II. Impact of angiotensin II on flow-dependent transport

Underlying glomerulotubular balance (GTB) is the impact of axial flow to regulate Na(+) and HCO(3)(-) transport by modulating Na(+)-H(+) exchanger 3 (NHE3) and H-ATPase activity. It is not known whether the cascade of events following a change in flow relies on local angiotensin (ANG II) generation or receptor availability. Mouse tubules were microperfused in vitro at flows of 5 and 20 nl/min, and net fluid (J(v)) and HCO(3)(-) (J(HCO3)) absorption and cell height were measured. Na(+) (J(Na)) and Cl(-) (J(Cl)) absorption and changes in microvillous torque were estimated. Raising flow increased Na(+) and HCO(3)(-) reabsorption but did not change either Cl(-) transport or cell volume. Losartan reduced absolute Na(+) and HCO(3)(-) absorption at both low and high flows but did not affect fractional flow-stimulated transport. Compared with controls, in AT(1a) knockout (KO) mouse tubules, 53% of flow-stimulated Na(+) absorption was abolished, but flow-stimulated HCO(3)(-) absorption was retained at similar levels. The remaining flow-stimulated J(HCO3) was eliminated by the H-ATPase inhibitor bafilomycin. Inhibition of the AT(2) receptor by PD123319 increased both J(Na) and J(HCO3) but did not affect flow-mediated fractional changes. NHE3 expression at the protein level was reduced in AT(1a) KO mice kidneys. We conclude that 1) although the AT(1a) receptor is necessary for flow to impact NHE3, the effect on H(+)-ATPase is independent of AT(1a); 2) the small flow-mediated changes in cell volume suggest a coordinate flow effect on both luminal and basolateral transporters; and 3) there is no evidence of flow-dependent Cl(-) transport, and thus no evidence for convective paracellular Cl(-) transport in mouse tubules.

Regulation of glomerulotubular balance. I. Impact of dopamine on flow-dependent transport

In response to volume expansion, locally generated dopamine decreases proximal tubule reabsorption by reducing both Na/H-exchanger 3 (NHE3) and Na-K-ATPase activity. We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na(+) and HCO(3)(-) reabsorption and have suggested that this observation underlies glomerulotubular balance. In the present work, we investigate the impact of dopamine on the sensitivity of reabsorptive fluxes to changes in luminal flow. Mouse proximal tubules were microperfused in vitro at low and high flow rates, and volume and HCO(3)(-) reabsorption (J(v) and J(HCO3)) were measured, while Na(+) and Cl(-) reabsorption (J(Na) and J(Cl)) were estimated. Raising luminal flow increased J(v), J(Na), and J(HCO3) but did not change J(Cl). Luminal dopamine did not change J(v), J(Na), and J(HCO3) at low flow rates but completely abolished the increments of Na(+) absorption by flow and partially inhibited the flow-stimulated HCO(3)(-) absorption. The remaining flow-stimulated HCO(3)(-) absorption was completely abolished by bafilomycin. The DA1 receptor blocker SCH23390 and the PKA inhibitor H89 blocked the effect of exogenous dopamine and produced a two to threefold increase in the sensitivity of proximal Na(+) reabsorption to luminal flow rate. Under the variety of perfusion conditions, changes in cell volume were small and did not always parallel changes in Na(+) transport. We conclude that 1) dopamine inhibits flow-stimulated NHE3 activity by activation of the DA1 receptor via a PKA-mediated mechanism; 2) dopamine has no effect on flow-stimulated H-ATPase activity; 3) there is no evidence of flow stimulation of Cl(-) reabsorption; and 4) the impact of dopamine is a coordinated modulation of both luminal and peritubular Na(+) transporters.

Angiotensin receptor blockers shift the circadian rhythm of blood pressure by suppressing tubular sodium reabsorption

Recently, we found that an angiotensin II receptor blocker (ARB) restored the circadian rhythm of the blood pressure (BP) from a nondipper to a dipper pattern, similar to that achieved with sodium intake restriction and diuretics (Fukuda M, Yamanaka T, Mizuno M, Motokawa M, Shirasawa Y, Miyagi S, Nishio T, Yoshida A, Kimura G. J Hypertens 26: 583-588, 2008). ARB enhanced natriuresis during the day, while BP was markedly lower during the night, resulting in the dipper pattern. In the present study, we examined whether the suppression of tubular sodium reabsorption, similar to the action of diuretics, was the mechanism by which ARB normalized the circadian BP rhythm. BP and glomerulotubular balance were compared in 41 patients with chronic kidney disease before and during ARB treatment with olmesartan once a day in the morning for 8 wk. ARB increased natriuresis (sodium excretion rate; U(Na)V) during the day (4.5 ± 2.2 to 5.5 ± 2.1 mmol/h, P = 0.002), while it had no effect during the night (4.3 ± 2.0 to 3.8 ± 1.6 mmol/h, P = 0.1). The night/day ratios of both BP and U(Na)V were decreased. The decrease in the night/day ratio of BP correlated with the increase in the daytime U(Na)V (r = 0.42, P = 0.006). Throughout the whole day, the glomerular filtration rate (P = 0.0006) and tubular sodium reabsorption (P = 0.0005) were both reduced significantly by ARB, although U(Na)V remained constant (107 ± 45 vs. 118 ± 36 mmol/day, P = 0.07). These findings indicate that the suppression of tubular sodium reabsorption, showing a resemblance to the action of diuretics, is the primary mechanism by which ARB can shift the circadian BP rhythm into a dipper pattern.

Mechanotransduction in the renal tubule

The role of mechanical forces in the regulation of glomerulotubular balance in the proximal tubule (PT) and Ca(2+) signaling in the distal nephron was first recognized a decade ago, when it was proposed that the microvilli in the PT and the primary cilium in the cortical collecting duct (CCD) acted as sensors of local tubular flow. In this review, we present a summary of the theoretical models and experiments that have been conducted to elucidate the structure and function of these unique apical structures in the modulation of Na(+), HCO(3)(-), and water reabsorption in the PT and Ca(2+) signaling in the CCD. We also contrast the mechanotransduction mechanisms in renal epithelium with those in other cells in which fluid shear stresses have been recognized to play a key role in initiating intracellular signaling, most notably endothelial cells, hair cells in the inner ear, and bone cells. In each case, small hydrodynamic forces need to be greatly amplified before they can be sensed by the cell's intracellular cytoskeleton to enable the cell to regulate its membrane transporters or stretch-activated ion channels in maintaining homeostasis in response to changing flow conditions.