Academic Editor:Yoshinori Marunaka
Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 5 May 2014; Accepted 16 May 2014; 28 May 2014
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction
Renal proximal tubules (PTs) reabsorb approximately 80% of the filtered bicarbonate from glomerulus, thereby playing a pivotal role in the maintenance of systemic acid-base balance [1]. This process is mostly dependent on Na+ , which is composed of the luminal Na+ /H+ exchanger and the basolateral Na+ -HCO3 - cotransporter [1]. Although distal nephron segments are also involved in the systemic acid/base regulation, acid-base transporters in these segments often cannot completely compensate for defects in bicarbonate absorption from PTs. Indeed, mutations in the Na+ -HCO3 - cotransporter NBCe1, which mediates a majority of bicarbonate exit from the basolateral membrane of PTs, are known to cause a severe type of proximal renal tubular acidosis associated with ocular and other extrarenal manifestations [2].
On the other hand, PTs reabsorb approximately 65% of the filtered NaCl, thereby also contributing to the regulation of plasma volume and blood pressure. For example, hypertension is frequently associated with metabolic syndrome, and insulin-mediated stimulation of PT transport may play a role in this association [3, 4]. In addition, angiotensin (Ang) II is pivotal in the regulation of blood pressure, and stimulation of PT transport may play a critical role in Ang II-mediated hypertension [5, 6]. In this review, we will focus on the roles of PT transport in the maintenance of acid-base homeostasis as well as the regulation of blood pressure.
2. Roles of PT Transport in Acid/Base Balance
In PTs, the luminal Na+ /H+ exchanger type 3 (NHE3) together with the basolateral Na+ -HCO3 - cotransporter NBCe1 is thought to mediate a majority of sodium-coupled bicarbonate absorption from this segment [1, 7]. Although the basolateral membrane of PTs contains Na+ -dependent and Na+ -independent Cl- /HCO3 - exchangers [7], these transporters cannot effectively compensate for the loss of NBCe1 function. By contrast, the loss of NHE3 function may be at least partially compensated by the other luminal transporters such as NHE8 [8].
In 1983 Boron and Boulpaep identified the functional existence of electrogenic Na+ -coupled HCO3 - transport activity in the basolateral membrane of isolated salamander PTs [9]. Subsequently, Kondo and Frömter revealed that this electrogenic Na+ -HCO3 - cotransport activity is robust in S1 and S2 segments but almost absent in S3 segment of isolated rabbit PTs [10]. Yoshitomi and colleagues initially reported that the Na+ -HCO3 - cotransporter in rat PTs in vivo functions with 1Na+ to 3HCO3 - stoichiometry [11]. On the other hand, Seki and colleagues revealed that the Na+ -HCO3 - cotransporter in isolated rabbit PTs functions with 1Na+ to 2HCO3 - stoichiometry [12]. Later, Müller-Berger and colleagues found that the Na+ -HCO3 - cotransporter in isolated rabbit PTs can change its transport stoichiometry depending on the incubation conditions [13]. Interestingly, NBCe1 expressed in Xenopus oocytes can also change its transport stoichiometry depending on changes in cytosolic Ca2+ concentrations [14]. Consistent with these data, Gross and colleagues reported that stoichiometry of NBCe1 is cell-type specific [15].
In 1997 Romero and colleagues succeeded in the first molecular cloning of NBCe1 from salamander kidney [16]. Among the three major variants, NBCe1A is transcribed from the alternative promoter in exon 1 and abundantly expressed in the basolateral membrane of PTs, representing the major bicarbonate exit pathway in this nephron segment [1]. Another variant NBCe1B is transcribed from the dominant promoter in exon 1 and differs from NBCe1A only at the N-terminus [17]. NBCe1B is first cloned from pancreas but is now known to be expressed in a variety of tissues such as intestinal tracts, ocular tissues, and brain [18-20]. On the other hand, NBCe1C is predominantly expressed in brain and differs from NBCe1B only at the C-terminus [21]. Consistent with the indispensable role of NBCe1 in acid/base homeostasis, Igarashi and colleagues found that inactivating mutations in NBCe1 cause a severe type of proximal renal tubular acidosis (pRTA) associated with ocular abnormalities [2]. Until now 12 different homozygous mutations have been found in pRTA patients [22]. These patients invariably presented with ocular abnormalities such as band keratopathy, cataract, and glaucoma, suggesting that NBCe1 function is essential for the maintenance of homeostasis in ocular tissues. Indeed, NBCe1 is found to be abundantly expressed in several human ocular tissues such as corneal endothelium, lens epithelium, and trabecular meshwork cells [20].
NBCe1 in brain may also play several physiological roles [23]. Indeed, Suzuki and colleagues revealed that defective membrane expression of NBCe1B may cause migraine with or without hemiplegia [24]. NBCe1B activity in astrocytes may be indispensable for the regulation of synaptic pH and neuron excitability.
Two types of NBCe1-deficient mice, NBCe1-KO mice [25] and W516X-knockin mice [26], present with very severe acidemia due to pRTA and die within 30 days. Functional analysis using isolated PTs from W516X-knockin mice confirmed that the normal NBCe1 activity is essential for bicarbonate absorption from this nephron segment [26]. Alkali therapy significantly prolonged the survival of W516X-knockin mice. Detailed analysis of ocular tissues in these mice revealed that NBCe1 plays a critical role in the maintenance of corneal transparency also in mice [26].
Unlike NBCe1-deficient mice, NHE3-KO mice present with only mild acidemia [27]. Although NHE8 seems to partially compensate for the loss of NHE3 function, NHE3/NHE3-double KO mice also present with relatively mild acidemia [8]. So far, mutations in NHE3 or NHE8 have not been found in human pRTA patients.
3. Roles of Hyperinsulinemia in Hypertension Associated with Metabolic Syndrome
Certain risk factors such as abdominal adiposity, glucose intolerance, dyslipidemia, and hypertension tend to cluster within individuals. Insulin resistance with obesity is thought to be a key factor for this association, which is now termed as metabolic syndrome [28]. Several different mechanisms such as activation of renin-angiotensin-aldosterone system (RAAS), enhancement of sympathetic nervous system, or hyperinsulinemia may be involved in the occurrence of hypertension associated with insulin resistance [29, 30]. Among these factors, hyperinsulinemia-induced hypertension seems to be an attractive hypothesis in view of the antinatriuretic action of insulin [3, 4]. Indeed, insulin is known to stimulate sodium absorption from several nephron segments. For example, insulin may stimulate sodium absorption from distal convoluted tubules by phosphorylating the Na+ -Cl- cotransporter NCC through the with-no-lysine kinase 4 (WNK4)/STE20/SPS1-related proline-alanine-rich kinase (SPAK) pathway [31]. In cortical collecting duct (CCD) cells insulin is thought to stimulate sodium absorption by activating the activity of epithelial Na+ channel ENaC [32-34], though a recent study failed to confirm the stimulatory effect of insulin on the ENaC activity in isolated mammalian CCD [35]. In PTs, insulin enhances sodium absorption by stimulating the luminal NHE3, the basolateral Na+ /K+ -ATPase, and the basolateral NBCe1 [36-39].
Insulin can relax vascular tones through the phosphatidylinositol 3 kinase (PI3K)/Akt-dependent nitric oxide (NO) production, and simple hyperinsulinemia may not necessarily induce hypertension [40]. Notably, however, the vasodilator action of insulin is reported to be attenuated in insulin resistance [41, 42]. Therefore, hyperinsulinemia can be an important factor in hypertension associated with metabolic syndrome, if the stimulatory effects of insulin on renal sodium absorption are preserved even in the systemic insulin resistance.
In support of this hypothesis, recent studies have clarified that defects in insulin signaling at the level of insulin receptor substrate (IRS) proteins are frequently associated with human insulin resistant states, resulting in the occurrence of cell-type specific insulin resistance [43, 44]. The two major substrates IRS1 and IRS2 may mediate distinct pathways in insulin signaling, and they are not functionally interchangeable in many insulin-sensitive tissues [43-45]. Importantly, in adipocytes of human subjects with noninsulin-dependent diabetes mellitus the expression of IRS1 protein is found to be markedly reduced, accompanied with the severe reduction of insulin-mediated glucose uptake [46]. By contrast, the reduction of IRS2 expression seems to be a key factor in several forms of insulin resistance in liver [47].
To clarify the relative importance of IRS1 and IRS2 in the stimulatory effect of insulin on PT transport, Zheng and colleagues compared the effects of insulin on sodium-coupled bicarbonate absorption in isolated PTs from IRS1-KO and IRS2-KO mice. They found that the PI3 K-dependent stimulatory effect of insulin on PT transport was preserved in IRS1-KO mice but markedly attenuated in IRS2-KO mice. Furthermore, insulin-induced Akt phosphorylation was also preserved in IRS1-KO mice but not in IRS-2 KO mice [48]. These results indicate that IRS2 is the main substrate that mediates the stimulatory effects of insulin on PT transport. Importantly, insulin can induce antinatriuresis even in insulin resistant rats and humans [49, 50]. Moreover, PT sodium transport seems to be enhanced in insulin resistant humans [51, 52], suggesting that the stimulatory effect of insulin on PT transport may be preserved in common forms of insulin resistance. Consistent with this view, a recent study showed that the expression of IRS2 as well as insulin-mediated Akt phosphorylation in renal tubules is preserved in Zucker fatty rats that show marked insulin resistance due to defective leptin signaling [53]. In liver, hyperinsulinemia is known to suppress the expression of IRS2, thereby attenuating the insulin signaling in liver [47, 54]. Future studies are required to determine whether the IRS2-dependent stimulatory insulin signaling in PTs is preserved in common forms of insulin resistance.
Interestingly, the IRS1-dependent insulin signaling in glomeruli seems to be attenuated in insulin resistance [53]. Because insulin signaling may be required not only for the nitric oxide (NO) production by glomerular endothelium but also for the preservation of normal podocyte functions [53, 55], insulin resistance in glomeruli may promote the occurrence and progression of diabetic nephropathy. In fact, the treatment with insulin sensitizers thiazolidinediones (TZDs) can protect podocyte from injury independently of glycemic control [56]. However, TZDs, especially when used with insulin, may induce edema formation as a side effect, probably by stimulating sodium absorption from PT and/or distal tubules [57, 58]. Unfortunately, this side effect may offset the beneficial effects of TZDs on the insulin signaling in glomeruli.
4. Effects of Ang II on PT Transport
There are two major Ang II receptors (AT), AT1 and AT2 . AT1 receptors are further subdivided into AT1A and AT1B in rodents [59]. While AT1 may be the main receptors that mediate the effects of Ang II on blood pressure, AT2 may be also partially involved in blood pressure regulation [60]. Ang II can regulate blood pressure via AT1 receptors in both renal and extrarenal tissues. To clarify the relative importance of these receptors in blood pressure homeostasis, Coffman and colleagues performed kidney cross-transplantation between wild-type and AT1A -KO mice [5, 6]. They found that renal and extrarenal AT1A receptors almost equally contribute to the maintenance of baseline blood pressure. However, renal AT1A receptors are indispensable for the occurrence of Ang II-induced hypertension and cardiac hypertrophy. They further showed that specific deletion of AT1A receptors from PTs alone is sufficient to lower blood pressure and provides substantial protection against Ang II-induced hypertension [61]. These results indicate that the stimulatory effect of Ang II on PT sodium transport is quite important in blood pressure regulation.
Paradoxically, however, the effects of Ang II on PT transport are biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II, while it is inhibited by nanomolar to micromolar concentrations of Ang II [62, 63]. The effects of Ang II on NHE3, Na+ /K+ ATPase, and NBCe1 in PTs are all known to be biphasic [64-67]. Notably, intrarenal concentrations of Ang II are much higher than those in plasma [68]. Accordingly, the inhibitory effect of Ang II on PT transport could have some physiological significance.
Controversial data have been reported as to the receptor subtype(s) responsible for the biphasic effects of Ang II on PT transport [69, 70]. However, Horita and colleagues, by analyzing the NBCe1 activity in isolated PTs, found that the biphasic effects of Ang II added to bath perfusate were lost in AT1A -KO mice [71]. Instead, very high concentrations of Ang II added to bath perfusate induced a slight stimulation of NBCe1 activity, which was probably mediated by AT1B [71, 72]. Zheng and colleagues, by analyzing the bicarbonate absorption rates from isolated PTs, also found that the biphasic effects of Ang II added to luminal perfusate were lost in AT1A -KO mice [73]. These results clearly indicate that both luminal and basolateral AT1A receptors mediate the biphasic effects of Ang II on PT transport.
Regarding the signaling pathways, the activation of PKC and/or the decrease in intracellular cAMP concentrations, which may ultimately result in ERK activation, are thought to mediate the stimulatory effect of Ang II [67, 72, 74]. On the other hand, the activation of phospholipase A2 (PLA2 )/arachidonic acid/5,6-epoxyeicosatrienoic acid (EET) pathway and/or the NO/cGMP pathway is thought to mediate the inhibitory effect of Ang II [67, 72, 75]. Consistent with this view, Li and colleagues found that the biphasic effects of Ang II were lost and all the concentrations of Ang II induced a similar stimulation of NBCe1 activity in isolated PTs from cytosolic PLA2 -KO mice [72].
While the biphasic effects of Ang II on PT transport have been reported in rats, mice, and rabbits [62, 63, 65, 66, 71, 73], little has been known about the effects of Ang II on human PT transport. To clarify this issue, Shirai and colleagues recently examined the effects of Ang II in isolated human PTs obtained from nephrectomy surgery for renal carcinoma [76]. Surprisingly, they found that Ang II, unlike that in the other species, induced a dose-dependent, profound stimulation of human PT transport via AT1 -dependent ERK activation. In wild-type mice, the inhibitory effect of Ang II was dependent on the NO/cGMP/cGMP-dependent kinase II (cGKII) pathway. In cGKII-KO mice, the inhibitory effect of Ang II was lost but the NO/cGMP pathway failed to induce the ERK-dependent NBCe1 activation. By sharp contrast, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II via cGKII-independent ERK activation. Thus, as shown in Figure 1, the contrasting responses to NO/cGMP pathway seem to be largely responsible for the different modes of PT transport regulation by Ang II in humans and the other species.
Figure 1: Ang II signaling in mouse and human PTs. In mouse PTs, low concentrations of Ang II induce transport stimulation via either PKC activation or decrease in intracellular cAMP resulting in ERK activation, while high concentrations of Ang II induce transport inhibition via NO/cGMP/cGKII pathway. In human PTs, by contrast, Ang II induces dose-dependent transport stimulation via NO/cGMP/ERK pathway.
[figure omitted; refer to PDF]
At present the molecular mechanisms underlying the species differences in PT response to NO/cGMP pathway remain unknown. However, previous studies suggest that such species differences may indeed exist. For example, NO is generally thought to work as inhibitory on PT transport in rodents [77, 78]. Furthermore, salt loading into rodents is known to enhance renal NO synthesis, which may facilitate sodium excretion and preservation of normal blood pressure [79, 80]. In human subjects, however, salt loading fails to induce an adaptive increase in renal NO synthesis [81, 82]. Thus, the role of NO/cGMP in adaptive natriuretic response to salt loading is clearly established in rodents but not in human subjects. Taken together with these considerations, the study by Shirai and colleagues [76] suggests that the unopposed, marked stimulation of PT transport by high intrarenal concentrations of Ang II may play an important role in the pathogenesis of human hypertension. Furthermore, the human-specific stimulatory effect of NO/cGMP pathway on PT transport may represent a novel therapeutic target in hypertension.
5. Conclusion
In this paper, we reviewed the physiological and pathophysiological roles of PT transport. Sodium-coupled bicarbonate absorption from PTs plays a critical role in the systemic acid/base balance. Indeed, inactivating mutations in NBCe1 cause severe pRTA associated with ocular and other extrarenal abnormalities. Sodium transport in PTs may also play an important role in blood pressure regulation. In particular, the stimulatory effect of insulin on PT transport may be involved in the pathogenesis of hypertension associated with metabolic syndrome. Unlike in other species, Ang II dose-dependently stimulates human PT transport via NO/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
[1] W. F. Boron, "Acid-base transport by the renal proximal tubule," Journal of the American Society of Nephrology , vol. 17, no. 9, pp. 2368-2382, 2006.
[2] T. Igarashi, J. Inatomi, T. Sekine, S. H. Cha, Y. Kanai, M. Kunimi, K. Tsukamoto, H. Satoh, M. Shimadzu, F. Tozawa, T. Mori, M. Shiobara, G. Seki, H. Endou, "Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities," Nature Genetics , vol. 23, no. 3, pp. 264-266, 1999.
[3] A. Natali, A. Q. Galvan, D. Santoro, N. Pecori, S. Taddei, A. Salvetti, E. Ferrannini, "Relationship between insulin release, antinatriuresis and hypokalaemia after glucose ingestion in normal and hypertensive man," Clinical Science , vol. 85, no. 3, pp. 327-335, 1993.
[4] A. Quinones-Galvan, E. Ferrannini, "Renal effects of insulin in man," Journal of Nephrology , vol. 10, no. 4, pp. 188-191, 1997.
[5] S. D. Crowley, S. B. Gurley, M. J. Herrera, P. Ruiz, R. Griffiths, A. P. Kumar, H.-S. Kim, O. Smithies, T. H. Le, T. M. Coffman, "Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney," Proceedings of the National Academy of Sciences of the United States of America , vol. 103, no. 47, pp. 17985-17990, 2006.
[6] S. D. Crowley, S. B. Gurley, M. I. Oliverio, A. K. Pazmino, R. Griffiths, P. J. Flannery, R. F. Spurney, H.-S. Kim, O. Smithies, T. H. Le, T. M. Coffman, "Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system," The Journal of Clinical Investigation , vol. 115, no. 4, pp. 1092-1099, 2005.
[7] R. J. Alpern, "Cell mechanisms of proximal tubule acidification," Physiological Reviews , vol. 70, no. 1, pp. 79-114, 1990.
[8] M. Baum, K. Twombley, J. Gattineni, C. Joseph, L. Wang, Q. Zhang, V. Dwarakanath, O. W. Moe, "Proximal tubule Na+ /H+ exchanger activity in adult NHE8-/- , NHE3-/- , and NHE3-/- /NHE8-/- mice," American Journal of Physiology: Renal Physiology , vol. 303, no. 11, pp. F1495-F1502, 2012.
[9] W. F. Boron, E. L. Boulpaep, "Intracellular pH regulation in the renal proximal tubule of the salamander: basolateral HCO3 - transport," The Journal of General Physiology , vol. 81, no. 1, pp. 53-94, 1983.
[10] Y. Kondo, E. Frömter, "Axial heterogeneity of sodium-bicarbonate cotransport in proximal straight tubule of rabbit kidney," Pflügers Archiv , vol. 410, no. 4-5, pp. 481-486, 1987.
[11] K. Yoshitomi, B. C. Burckhardt, E. Frömter, "Rheogenic sodium-bicarbonate cotransport in the peritubular cell membrane of rat renal proximal tubule," Pflügers Archiv , vol. 405, no. 4, pp. 360-366, 1985.
[12] G. Seki, S. Coppola, E. Frömter, "The Na+ -HCO3 - cotransporter operates with a coupling ratio of 2 HCO3 - to 1 Na+ in isolated rabbit renal proximal tubule," Pflügers Archiv , vol. 425, no. 5-6, pp. 409-416, 1993.
[13] S. Müller-Berger, V. V. Nesterov, E. Frömter, "Partial recovery of in vivo function by improved incubation conditions of isolated renal proximal tubule. II. Change of Na-HCO3 cotransport stoichiometry and of response to acetazolamide," Pflügers Archiv , vol. 434, no. 4, pp. 383-391, 1997.
[14] S. Müller-Berger, O. Ducoudret, A. Diakov, E. Frömter, "The renal Na-HCO3 -cotransporter expressed in Xenopus laevis oocytes: change in stoichiometry in response to elevation of cytosolic Ca2+ concentration," Pflügers Archiv , vol. 442, no. 5, pp. 718-728, 2001.
[15] E. Gross, K. Hawkins, N. Abuladze, A. Pushkin, C. U. Cotton, U. Hopfer, I. Kurtz, "The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent," The Journal of Physiology , vol. 531, no. 3, pp. 597-603, 2001.
[16] M. F. Romero, M. A. Hediger, E. L. Boulpaep, W. F. Boron, "Expression cloning and characterization of a renal electrogenic Na+ /HCO3- cotransporter," Nature , vol. 387, no. 6631, pp. 409-413, 1997.
[17] N. Abuladze, M. Song, A. Pushkin, D. Newman, I. Lee, S. Nicholas, I. Kurtz, "Structural organization of the human NBC1 gene: kNBC1 is transcribed from an alternative promoter in intron 3," Gene , vol. 251, no. 2, pp. 109-122, 2000.
[18] N. Abuladze, I. Lee, D. Newman, J. Hwang, K. Boorer, A. Pushkin, I. Kurtz, "Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter," The Journal of Biological Chemistry , vol. 273, no. 28, pp. 17689-17695, 1998.
[19] M. F. Romero, W. F. Boron, "Electrogenic Na+ /HCO3 - cotransporters: cloning and physiology," Annual Review of Physiology , vol. 61, pp. 699-723, 1999.
[20] T. Usui, M. Hara, H. Satoh, N. Moriyama, H. Kagaya, S. Amano, T. Oshika, Y. Ishii, N. Ibaraki, C. Hara, M. Kunimi, E. Noiri, K. Tsukamoto, J. Inatomi, H. Kawakami, H. Endou, T. Igarashi, A. Goto, T. Fujita, M. Araie, G. Seki, "Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis," The Journal of Clinical Investigation , vol. 108, no. 1, pp. 107-115, 2001.
[21] M. O. Bevensee, B. M. Schmitt, I. Choi, M. F. Romero, W. F. Boron, "An electrogenic Na+ -HCO3 - cotransporter (NBC) with a novel COOH-terminus, cloned from rat brain," American Journal of Physiology: Cell Physiology , vol. 278, no. 6, pp. C1200-C1211, 2000.
[22] G. Seki, S. Horita, M. Suzuki, "Molecular mechanisms of renal and extrarenal manifestations caused by inactivation of the electrogenic Na-HCO3 cotransporter NBCe1," Frontiers in Physiology , vol. 4, no. 270, pp. 1-8, 2013.
[23] M. Chesler, "Regulation and modulation of pH in the brain," Physiological Reviews , vol. 83, no. 4, pp. 1183-1221, 2003.
[24] M. Suzuki, W. van Paesschen, I. Stalmans, S. Horita, H. Yamada, B. A. Bergmans, E. Legius, F. Riant, P. de Jonghe, Y. Li, T. Sekine, T. Igarashi, I. Fujimoto, K. Mikoshiba, M. Shimadzu, M. Shiohara, N. Braverman, L. Al-Gazali, T. Fujita, G. Seki, "Defective membrane expression of the Na+ -HCO3 - cotransporter NBCe1 is associated with familial migraine," Proceedings of the National Academy of Sciences of the United States of America , vol. 107, no. 36, pp. 15963-15968, 2010.
[25] L. R. Gawenis, E. M. Bradford, V. Prasad, J. N. Lorenz, J. E. Simpson, L. L. Clarke, A. L. Woo, C. Grisham, L. P. Sanford, T. Doetschman, M. L. Miller, G. E. Shull, "Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na+ /HCO3 - cotransporter," The Journal of Biological Chemistry , vol. 282, no. 12, pp. 9042-9052, 2007.
[26] Y.-F. Lo, S.-S. Yang, G. Seki, H. Yamada, S. Horita, O. Yamazaki, T. Fujita, T. Usui, J.-D. Tsai, I.-S. Yu, S.-W. Lin, S.-H. Lin, "Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis," Kidney International , vol. 79, no. 7, pp. 730-741, 2011.
[27] P. J. Schultheis, L. L. Clarke, P. Meneton, M. L. Miller, M. Soleimani, L. R. Gawenis, T. M. Riddle, J. J. Duffy, T. Doetschman, T. Wang, G. Giebisch, P. S. Aronson, J. N. Lorenz, G. E. Shull, "Renal and intestinal absorptive defects in mice lacking the NHE3 Na+ /H+ exchanger," Nature Genetics , vol. 19, no. 3, pp. 282-285, 1998.
[28] J. Levesque, B. Lamarche, "The metabolic syndrome: definitions, prevalence and management," Journal of Nutrigenetics and Nutrigenomics , vol. 1, no. 3, pp. 100-108, 2008.
[29] F. A. El-Atat, S. N. Stas, S. I. Mcfarlane, J. R. Sowers, "The relationship between hyperinsulinemia, hypertension and progressive renal disease," Journal of the American Society of Nephrology , vol. 15, no. 11, pp. 2816-2827, 2004.
[30] J. E. Hall, D. A. Hildebrandt, J. Kuo, "Obesity hypertension: role of leptin and sympathetic nervous system," American Journal of Hypertension , vol. 14, no. 6, part 2, pp. 103S-115S, 2001.
[31] E. Sohara, T. Rai, S.-S. Yang, A. Ohta, S. Naito, M. Chiga, N. Nomura, S.-H. Lin, A. Vandewalle, E. Ohta, S. Sasaki, S. Uchida, "Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney," PLoS ONE , vol. 6, no. 8, article e24277, 2011.
[32] B. L. Blazer-Yost, M. A. Esterman, C. J. Vlahos, "Insulin-stimulated trafficking of ENaC in renal cells requires PI 3-kinase activity," American Journal of Physiology: Cell Physiology , vol. 284, no. 6, pp. C1645-C1653, 2003.
[33] Y. Marunaka, N. Hagiwara, H. Tohda, "Insulin activates single amiloride-blockable Na channels in a distal nephron cell line (A6)," American Journal of Physiology: Renal Fluid and Electrolyte Physiology , vol. 263, no. 3, part 2, pp. F392-F400, 1992.
[34] S. Tiwari, S. Riazi, C. A. Ecelbarger, "Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes," American Journal of Physiology: Renal Physiology , vol. 293, no. 4, pp. F974-F984, 2007.
[35] G. Frindt, L. G. Palmer, "Effects of insulin on Na and K transporters in the rat CCD," American Journal of Physiology: Renal Physiology , vol. 302, no. 10, pp. F1227-F1233, 2012.
[36] M. Baum, "Insulin stimulates volume absorption in the rabbit proximal convoluted tubule," The Journal of Clinical Investigation , vol. 79, no. 4, pp. 1104-1109, 1987.
[37] E. Feraille, M. L. Carranza, M. Rousselot, H. Favre, "Insulin enhances sodium sensitivity of Na-K-ATPase in isolated rat proximal convoluted tubule," American Journal of Physiology: Renal Fluid and Electrolyte Physiology , vol. 267, no. 1, part 2, pp. F55-F62, 1994.
[38] F. A. Gesek, A. C. Schoolwerth, "Insulin increases Na+ -H+ exchange activity in proximal tubules from normotensive and hypertensive rats," American Journal of Physiology: Renal Fluid and Electrolyte Physiology , vol. 260, no. 5, part 2, pp. F695-F703, 1991.
[39] O. S. Ruiz, Y.-Y. Qiu, L. R. Cardoso, J. A. Arruda, "Regulation of the renal Na-HCO3 cotransporter: IX. Modulation by insulin, epidermal growth factor and carbachol," Regulatory Peptides , vol. 77, no. 1-3, pp. 155-161, 1998.
[40] J. E. Hall, "Hyperinsulinemia: a link between obesity and hypertension?," Kidney International , vol. 43, no. 6, pp. 1402-1417, 1993.
[41] J.-A. Kim, M. Montagnani, K. K. Kwang, M. J. Quon, "Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms," Circulation , vol. 113, no. 15, pp. 1888-1904, 2006.
[42] H. O. Steinberg, H. Chaker, R. Leaming, A. Johnson, G. Brechtel, A. D. Baron, "Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance," The Journal of Clinical Investigation , vol. 97, no. 11, pp. 2601-2610, 1996.
[43] M. Benito, "Tissue-specificity of insulin action and resistance," Archives of Physiology and Biochemistry , vol. 117, no. 3, pp. 96-104, 2011.
[44] S. B. Biddinger, C. R. Kahn, "From mice to men: insights into the insulin resistance syndromes," Annual Review of Physiology , vol. 68, pp. 123-158, 2006.
[45] A. Nandi, Y. Kitamura, C. R. Kahn, D. Accili, "Mouse models of insulin resistance," Physiological Reviews , vol. 84, no. 2, pp. 623-647, 2004.
[46] C. M. Rondinone, L.-M. Wang, P. Lonnroth, C. Wesslau, J. H. Pierce, U. Smith, "Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus," Proceedings of the National Academy of Sciences of the United States of America , vol. 94, no. 8, pp. 4171-4175, 1997.
[47] I. Shimomura, M. Matsuda, R. E. Hammer, Y. Bashmakov, M. S. Brown, J. L. Goldstein, "Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice," Molecular Cell , vol. 6, no. 1, pp. 77-86, 2000.
[48] Y. Zheng, H. Yamada, K. Sakamoto, S. Horita, M. Kunimi, Y. Endo, Y. Li, K. Tobe, Y. Terauchi, T. Kadowaki, G. Seki, T. Fujita, "Roles of insulin receptor substrates in insulin-induced stimulation of renal proximal bicarbonate absorption," Journal of the American Society of Nephrology , vol. 16, no. 8, pp. 2288-2295, 2005.
[49] C. Catena, A. Cavarape, M. Novello, G. Giacchetti, L. A. Sechi, "Insulin receptors and renal sodium handling in hypertensive fructose-fed rats," Kidney International , vol. 64, no. 6, pp. 2163-2171, 2003.
[50] P. Skott, A. Vaag, N. E. Bruun, O. Hother-Nielsen, M.-A. Gall, H. Beck-Nielsen, H.-H. Parving, "Effect of insulin on renal sodium handlings in hyperinsulinaemic type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance," Diabetologia , vol. 34, no. 4, pp. 275-281, 1991.
[51] P. Strazzullo, G. Barba, F. P. Cappuccio, A. Siani, M. Trevisan, E. Farinaro, E. Pagano, A. Barbato, R. Iacone, F. Galletti, "Altered renal sodium handling in men with abdominal adiposity: a link to hypertension," Journal of Hypertension , vol. 19, no. 12, pp. 2157-2164, 2001.
[52] P. Strazzullo, A. Barbato, F. Galletti, G. Barba, A. Siani, R. Iacone, L. D'Elia, O. Russo, M. Versiero, E. Farinaro, F. P. Cappuccio, "Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study," Journal of Hypertension , vol. 24, no. 8, pp. 1633-1639, 2006.
[53] A. Mima, Y. Ohshiro, M. Kitada, M. Matsumoto, P. Geraldes, C. Li, Q. Li, G. S. White, C. Cahill, C. Rask-Madsen, G. L. King, "Glomerular-specific protein kinase C-Β -induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity," Kidney International , vol. 79, no. 8, pp. 883-896, 2011.
[54] J. Zhang, J. Ou, Y. Bashmakov, J. D. Horton, M. S. Brown, J. L. Goldstein, "Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes," Proceedings of the National Academy of Sciences of the United States of America , vol. 98, no. 7, pp. 3756-3761, 2001.
[55] G. I. Welsh, L. J. Hale, V. Eremina, M. Jeansson, Y. Maezawa, R. Lennon, D. A. Pons, R. J. Owen, S. C. Satchell, M. J. Miles, C. J. Caunt, C. A. McArdle, H. Pavenstädt, J. M. Tavaré, A. M. Herzenberg, C. R. Kahn, P. W. Mathieson, S. E. Quaggin, M. A. Saleem, R. J. M. Coward, "Insulin signaling to the glomerular podocyte is critical for normal kidney function," Cell Metabolism , vol. 12, no. 4, pp. 329-340, 2010.
[56] T. Kanjanabuch, L.-J. Ma, J. Chen, A. Pozzi, Y. Guan, P. Mundel, A. B. Fogo, "PPAR-γ agonist protects podocytes from injury," Kidney International , vol. 71, no. 12, pp. 1232-1239, 2007.
[57] Y. Endo, M. Suzuki, H. Yamada, S. Horita, M. Kunimi, O. Yamazaki, A. Shirai, M. Nakamura, N. Iso-O, Y. Li, M. Hara, K. Tsukamoto, N. Moriyama, A. Kudo, H. Kawakami, T. Yamauchi, N. Kubota, T. Kadowaki, H. Kume, Y. Enomoto, Y. Homma, G. Seki, T. Fujita, "Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ -dependent nongenomic signaling," Cell Metabolism , vol. 13, no. 5, pp. 550-561, 2011.
[58] V. Vallon, E. Hummler, T. Rieg, O. Pochynyuk, V. Bugaj, J. Schroth, G. Dechenes, B. Rossier, R. Cunard, J. Stockand, "Thiazolidinedione-induced fluid retention is independent of collecting duct α ENaC activity," Journal of the American Society of Nephrology , vol. 20, no. 4, pp. 721-729, 2009.
[59] T. Inagami, D. F. Guo, Y. Kitami, "Molecular biology of angiotensin II receptors: an overview," Journal of Hypertension. Supplement , vol. 12, no. 10, pp. S83-S94, 1994.
[60] T. Ichiki, P. A. Labosky, C. Shiota, S. Okuyama, Y. Imagawa, A. Fogo, F. Niimura, I. Ichikawa, B. L. M. Hogan, T. Inagami, "Effects on blood pressure exploratory behaviour of mice lacking angiotensin II type-2 receptor," Nature , vol. 377, no. 6551, pp. 748-750, 1995.
[61] S. B. Gurley, A. D. Riquier-Brison, J. Schnermann, M. A. Sparks, A. M. Allen, V. H. Haase, J. N. Snouwaert, T. H. Le, A. A. McDonough, B. H. Koller, T. M. Coffman, " A T 1A angiotensin receptors in the renal proximal tubule regulate blood pressure," Cell Metabolism , vol. 13, no. 4, pp. 469-475, 2011.
[62] P. J. Harris, J. A. Young, "Dose dependent stimulation and inhibition of proximal tubular sodium reabsorption by angiotensin II in the rat kidney," Pflügers Archiv , vol. 367, no. 3, pp. 295-297, 1977.
[63] V. L. Schuster, J. P. Kokko, H. R. Jacobson, "Angiotensin II directly stimulates sodium transport in rabbit proximal convoluted tubules," The Journal of Clinical Investigation , vol. 73, no. 2, pp. 507-515, 1984.
[64] A. A. Banday, M. F. Lokhandwala, "Loss of biphasic effect on Na/K-ATPase activity by angiotensin II involves defective angiotensin type 1 receptor-nitric oxide signaling," Hypertension , vol. 52, no. 6, pp. 1099-1105, 2008.
[65] S. Coppola, E. Frömter, "An electrophysiological study of angiotensin II regulation of Na-HCO3 cotransport and K conductance in renal proximal tubules. I. Effect of picomolar concentrations," Pflügers Archiv , vol. 427, no. 1-2, pp. 143-150, 1994.
[66] S. Coppola, E. Frömter, "An electrophysiological study of angiotensin II regulation of Na-HCO3 cotransport and K conductance in renal proximal tubules. II. Effect of micromolar concentrations," Pflügers Archiv , vol. 427, no. 1-2, pp. 151-156, 1994.
[67] P. Houillier, R. Chambrey, J. M. Achard, M. Froissart, J. Poggioli, M. Paillard, "Signaling pathways in the biphasic effect of angiotensin II on apical Na/H antiport activity in proximal tubule," Kidney International , vol. 50, no. 5, pp. 1496-1505, 1996.
[68] L. G. Navar, L. M. Harrison-Bernard, C.-T. Wang, L. Cervenka, K. D. Mitchell, "Concentrations and actions of intraluminal angiotensin II,", supplement 11 Journal of the American Society of Nephrology , vol. 10, pp. S189-S195, 1999.
[69] D. Haithcock, H. Jiao, X.-L. Cui, U. Hopper, J. G. Douglas, "Renal proximal tubular AT2 receptor: signaling and transport,", supplement 11 Journal of the American Society of Nephrology , vol. 10, pp. S69-S74, 1999.
[70] J. Poggioli, G. Lazar, P. Houillier, J. P. Gardin, J. M. Achard, M. Paillard, "Effects of angiotensin II and nonpeptide receptor antagonists on transduction pathways in rat proximal tubule," American Journal of Physiology: Cell Physiology , vol. 263, no. 4, part 1, pp. C750-C758, 1992.
[71] S. Horita, Y. Zheng, C. Hara, H. Yamada, M. Kunimi, S. Taniguchi, S. Uwatoko, T. Sugaya, A. Goto, T. Fujita, G. Seki, "Biphasic regulation of Na+ -HCO3 - cotransporter by angiotensin II type 1A receptor," Hypertension , vol. 40, no. 5, pp. 707-712, 2002.
[72] Y. Li, H. Yamada, Y. Kita, M. Kunimi, S. Horita, M. Suzuki, Y. Endo, T. Shimizu, G. Seki, T. Fujita, "Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+ -HCO3 - transport," Journal of the American Society of Nephrology , vol. 19, no. 2, pp. 252-259, 2008.
[73] Y. Zheng, S. Horita, C. Hara, M. Kunimi, H. Yamada, T. Sugaya, A. Goto, T. Fujita, G. Seki, "Biphasic regulation of renal proximal bicarbonate absorption by luminal AT1A receptor," Journal of the American Society of Nephrology , vol. 14, no. 5, pp. 1116-1122, 2003.
[74] F.-Y. Liu, M. G. Cogan, "Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate," The Journal of Clinical Investigation , vol. 84, no. 1, pp. 83-91, 1989.
[75] C. Zhang, P. R. Mayeux, "NO/cGMP signaling modulates regulation of Na+ -K+ -ATPase activity by angiotensin II in rat proximal tubules," American Journal of Physiology: Renal Physiology , vol. 280, no. 3, pp. F474-F479, 2001.
[76] A. Shirai, O. Yamazaki, S. Horita, "Angiotensin II dose-dependently stimulates human renal proximal tubule transport by the nitric oxide/guanosine 3[variant prime], 5[variant prime]-cyclic monophosphate pathway," Journal of the American Society of Nephrology , 2014.
[77] M. Liang, F. G. Knox, "Production and functional roles of nitric oxide in the proximal tubule," American Journal of Physiology: Regulatory Integrative and Comparative Physiology , vol. 278, no. 5, pp. R1117-R1124, 2000.
[78] P. A. Ortiz, J. L. Garvin, "Cardiovascular and renal control in NOS-deficient mouse models," American Journal of Physiology: Regulatory Integrative and Comparative Physiology , vol. 284, no. 3, pp. R628-R638, 2003.
[79] P. J. Shultz, J. P. Tolins, "Adaptation to increased dietary salt intake in the rat. Role of endogenous nitric oxide," The Journal of Clinical Investigation , vol. 91, no. 2, pp. 642-650, 1993.
[80] J. P. Tolins, P. J. Shultz, "Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt," Kidney International , vol. 46, no. 1, pp. 230-236, 1994.
[81] F. S. Facchini, C. DoNascimento, G. M. Reaven, J. W. Yip, X. P. Ni, M. H. Humphreys, "Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion," Hypertension , vol. 33, no. 4, pp. 1008-1012, 1999.
[82] R. J. Schmidt, W. H. Beierwaltes, C. Baylis, "Effects of aging and alterations in dietary sodium intake on total nitric oxide production," American Journal of Kidney Diseases , vol. 37, no. 5, pp. 900-908, 2001.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Copyright © 2014 Motonobu Nakamura et al. Motonobu Nakamura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Sodium-coupled bicarbonate absorption from renal proximal tubules (PTs) plays a pivotal role in the maintenance of systemic acid/base balance. Indeed, mutations in the Na+-HC[superscript][subscript]O3[/subscript] -[/superscript] cotransporter NBCe1, which mediates a majority of bicarbonate exit from PTs, cause severe proximal renal tubular acidosis associated with ocular and other extrarenal abnormalities. Sodium transport in PTs also plays an important role in the regulation of blood pressure. For example, PT transport stimulation by insulin may be involved in the pathogenesis of hypertension associated with insulin resistance. Type 1 angiotensin (Ang) II receptors in PT are critical for blood pressure homeostasis. Paradoxically, the effects of Ang II on PT transport are known to be biphasic. Unlike in other species, however, Ang II is recently shown to dose-dependently stimulate human PT transport via nitric oxide/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension. In this paper, we will review the physiological and pathophysiological roles of PT transport.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer