Effects of angiotensin II on the CO 2 dependence of HCO 3 − reabsorption by the rabbit S2 renal proximal tubule

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Zhou Y, Bouyer P, Boron WF. Role of the AT1A receptor in the CO 2-induced stimulation of HCO 3 Ϫ reabsorption by renal proximal tubules. Am J Physiol Renal Physiol 293: F110-F120, 2007. First published March 13, 2007; doi:10.1152/ajprenal.00516.2006.-The proximal tubule (PT) is major site for the reabsorption of filtered HCO 3 Ϫ . Previous work on the rabbit PT showed that 1) increases in basolateral (BL) CO 2 concentration ([CO2]BL) raise the HCO 3 Ϫ reabsorption rate (J HCO 3 ), and 2) the increase that luminal angiotensin II (ANG II) produces in J HCO 3 is greatest at 0% [CO2]BL and falls to nearly zero at 20%. Here, we investigate the role of angiotensin receptors in the [CO2]BL dependence of JHCO 3 in isolated perfused PTs. We found that, in rabbit S2 PT segments, luminal 10 Ϫ8 M saralasin (peptide antagonist of ANG II receptors), lowers baseline JHCO 3 (5% CO2) to the value normally seen at 0% in the absence of inhibitors and eliminates the JHCO 3 response to changes in [CO2]BL. However, basolateral 10 Ϫ8 M saralasin has no effect. As with saralasin, luminal 10 Ϫ8 M candesartan (AT1 antagonist) reduces baseline JHCO 3 and eliminates the [CO2]BL dependence of JHCO 3 . Luminal 10 Ϫ7 M PD 123319 (AT2 antagonist) has no effect. Finally, we compared PTs from wild-type and AT1A-null mice of the same genetic background. Knocking out AT1A modestly lowers baseline JHCO 3 and, like luminal saralasin or candesartan in rabbits, eliminates the JHCO 3 response to changes in [CO2]BL. Our accumulated evidence suggests that ANG II endogenous to the PT binds to the apical AT1A receptor and that this interaction is critical for both baseline JHCO 3 and its response to changes in [CO2]BL. Neither apical AT2 receptors nor basolateral ANG II receptors are involved in these processes. kidney; angiotensin; acid-base; out-of-equilibrium CO 2/HCO3 Ϫ solutions; fluid reabsorption THE KIDNEY PLAYS A KEY ROLE in regulating the volume and acid-base balance of the extracellular fluid. For example, in response to acute respiratory acidosis (i.e., a rise in PCO 2 that causes a fall in pH), the kidney rapidly stimulates H ϩ secretion, as shown in the 1950s by Relman et al. (62), Brazeau and Gilman (10), and Dorman et al. (21). The response occurs even in the denervated kidney (81). Moreover, acute respiratory alkalosis inhibits H ϩ secretion (45). Part of the response to respiratory acidosis is mediated by the renal proximal tubule (PT), which reabsorbs a near-isosmotic fluid that represents about two-thirds of the fluid and ϳ80% of the HCO 3 Ϫ filtered by the glomerulus. The PT cell actively secretes H ϩ into the tubule lumen (2, 7, 71) and uses this H ϩ to titrate filtered HCO 3 Ϫ in the lumen to CO 2 and H 2 O, catalyzed by apical carbonic anhydrase IV (11,72,74 Ϫ ] (90). In addition to acid-base disturbances, another powerful modulator of PT acid-base transport is angiotensin II (ANG II). Many investigators have shown that ANG II, added to the apical or basolateral solution, has a biphasic concentration-dependent effect on the rates of...

supporting

confidence: 88%

Section: Endogenous Angiotensin Production By Pt Cellsmentioning

confidence: 88%

Section: Effect Of Orthograde Vs Retrograde Perfusion On J Hco 3 Andmentioning

confidence: 95%

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Role of the AT_1Areceptor in the CO₂-induced stimulation of HCO₃⁻reabsorption by renal proximal tubules

Zhou¹,

Bouyer²,

Boron³

2007

Self Cite

“…The values that we report for J HCO 3 (or JV) in the second collection period are normalized, mean values computed as described previously (60,61). Briefly, in each experiment, we divided the J HCO 3 (or JV) value obtained during the second collection period by the comparable value obtained during the first collection period; the result was a pair of second/first collection period ratios.…”

Section: Discussionmentioning

confidence: 99%

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules

Zhou¹,

Bouyer²,

Boron³

2006

Self Cite

. Role of a tyrosine kinase in the CO 2-induced stimulation of HCO 3 Ϫ reabsorption by rabbit S2 proximal tubules. Am J Physiol Renal Physiol 291: F358 -F367, 2006; doi:10.1152/ajprenal.00520.2005.-A previous study demonstrated that proximal tubule cells regulate HCO 3 Ϫ reabsorption by sensing acute changes in basolateral CO2 concentration, suggesting that there is some sort of CO2 sensor at or near the basolateral membrane (Zhou Y, Zhao J, Bouyer P, and Boron WF Proc Natl Acad Sci USA 102: 3875-3880, 2005). Here, we hypothesized that an early element in the CO 2 signal-transduction cascade might be either a receptor tyrosine kinase (RTK) or a receptorassociated (or soluble) tyrosine kinase (sTK). In our experiments, we found, first, that basolateral 17.5 M genistein, a broad-spectrum tyrosine kinase inhibitor, virtually eliminates the CO 2 sensitivity of HCO 3 Ϫ absorption rate (J HCO 3 ). Second, we found that neither basolateral 250 nM nor basolateral 2 M PP2, a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK, reduces the CO 2-stimulated increase in J HCO 3 . Third, we found that either basolateral 35 nM PD168393, a high-affinity inhibitor of RTKs in the erbB (i.e., EGF receptor) family, or basolateral 10 nM BPIQ-I, which blocks erbB RTKs by competing with ATP, eliminates the CO2 sensitivity. In conclusion, the transduction of the CO2 signal requires activation of a tyrosine kinase, perhaps an erbB. The possibilities include the following: 1) a TK is simply permissive for the effect of CO 2 on J HCO 3 ; 2) a CO2 receptor activates an sTK, which would then raise J HCO 3 ; 3) a CO2 receptor transactivates an RTK; and 4) the CO2 receptor could itself be an RTK.kidney; out-of-equilibrium solutions; acid-base; volume reabsorption; signal transduction RENAL TUBULE CELLS PLAY A central role in whole body acid-base balance by 1) secreting H ϩ into the tubule lumen, thereby titrating NH 3 to NH 4 ϩ and also creating titratable acid; and 2) moving an equivalent amount of "new HCO 3 Ϫ " into the blood, ϳ70 mmol/day in humans, and thereby titrating the fixed acid produced by metabolism and generated by the gastrointestinal tract. At the same time, the tubules must also reabsorb nearly all of a much larger amount of HCO 3 Ϫ filtered in the glomeruli. The proximal tubule (PT) is the site of generation of ϳ60% of the new HCO 3 Ϫ and the site of reabsorption of ϳ80% of the filtered HCO 3 Ϫ , using the same transporters in both processes. The cell uses cytosolic carbonic anhydrase II (51, 52) to convert CO 2 ϩ H 2 O to H ϩ ϩ HCO 3 Ϫ , and then extrudes the H ϩ across the apical membrane (3, 10, 50) via Na/H exchangers (6, 7, 34) and H ϩ pumps (22) and exports the HCO 3 Ϫ across the basolateral membrane, mainly via the electrogenic Na-HCO 3 cotransporter (11,16,47,48). For the system to work properly, the PT cell must be able to respond to changes in whole body acid-base status by appropriately adjusting transporters activities.To study how the PT senses changes in whole bo...

“…Our protocol was virtually identical to the one that we used in previous studies (32)(33)(34)(35) except that, in the present study, we added lisinopril (a gift from Merck, Rahway, NJ), a specific ACE inhibitor, to the luminal or basolateral solution.…”

Section: Methodsmentioning

confidence: 99%

Role of endogenously secreted angiotensin II in the CO₂-induced stimulation of HCO₃reabsorption by renal proximal tubules

Zhou¹,

Boron²

2008

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Previous studies demonstrated that the proximal tubule (PT) responds to isolated increases in basolateral ([CO(2)](BL)) or "bath" CO(2) concentration by increasing the HCO(3)(-) reabsorption rate (J(HCO(3))). Blockade of the rabbit apical AT(1) receptor or knockout of the mouse AT(1A) receptor eliminates these effects, demonstrating a requirement for luminal ANG II that the PT itself synthesizes. In the present study, we examined the effects of the ACE inhibitor lisinopril on J(HCO(3)) in isolated perfused rabbit PTs (S2 segment), using out-of-equilibrium solutions to make isolated changes in [CO(2)](BL) at a fixed baseline HCO(3)(-) concentration of 22 mM and fixed baseline pH of 7.4. Adding 60 or 240 nM lisinopril (in vitro K(i): 0.5 or 1.2 nM) to the lumen had no effect. These results are not consistent with the hypothesis that the PT secretes either angiotensinogen or ANG I. However, adding 60 nM basolateral lisinopril significantly decreased J(HCO(3)) at a [CO(2)](BL) of 20%. Moreover, 240 nM basolateral lisinopril decreased baseline (i.e., at 5% CO(2)) J(HCO(3)) by one-half and completely eliminated the response to altering [CO(2)](BL) from 0 to 20%, but left intact the stimulatory effect of 10(-11) M basolateral ANG II. At extremely high concentrations (i.e., 100 microM), luminal lisinopril replicated the effects of 240 nM basolateral lisinopril. Our data are consistent with the hypothesis that lisinopril readily crosses the basolateral (but not apical) membrane to block ACE in a vesicular compartment. We conclude that the isolated PT predominantly secretes preformed ANG II, rather than angiotensinogen or ANG I.