Fig. 37.5 shows the localization of G protein-coupled H+ receptor (GPCR-GPR4) in the collecting duct. Activation of this receptor by an increase in extracellular fluid (ECF) [H+] stimulates H+ secretion. In the collecting duct, B or β-intercalated cells (ICs) secrete HCO3- and express a basolateral insulin-related receptor (IRR) that acts as a tyrosine kinase. This receptor is activated by an increase in ECF [HCO3-] and stimulates HCO3- secretion by the cell. Intracellular HCO3- also regulates a soluble adenylyl cyclase (sAC), which appears to play a role in regulating collecting duct H+ secretion. In the proximal tubule, basolateral membrane receptor tyrosine kinases (ErbB1 and ErbB2) sense changes in ECF PCO2. Activation of these receptors by an increase in PCO2 leads to the generation of angiotensin II. Angiotensin II acts from the lumen via AT-1A receptors and stimulates H+ secretion/HCO3- reabsorption. Additionally, in the proximal tubule, the non-receptor tyrosine kinase (Pyk2) senses intracellular [H+]. When activated by an increase in intracellular [H+], it stimulates H+ secretion/HCO3- reabsorption. Changes in extracellular or intracellular pH also affect the gating of ion channels, such as the renal outer medullary K+ channel (ROMK), which can serve as cellular acid-base sensors.

While some of the effects mentioned above can be directly attributed to acidosis, many of the changes in cellular H+ transport are mediated by hormones or other factors. Endothelin, cortisol, and angiotensin II are three known mediators of the renal response to acidosis. In the proximal tubule, metabolic acidosis increases the transport kinetics of the Na+/H+ antiporter (NHE3) and enhances the expression of the Na+/H+ antiporter, H+-ATPase, and the basolateral Na+/3HCO3- symporter (NBCe1) on the apical membrane. In the collecting duct, acidosis leads to the exocytic insertion of H+-ATPase into the apical membrane of intercalated cells. With long-term acidosis, the abundance of key acid-base transporters is increased in the proximal tubule (NHE3 and NBCe1) and collecting duct intercalated cells (H+-ATPase and AE1). Lastly, acidosis decreases the expression of the Cl-/HCO3- antiporter pendrin in HCO3--secreting intercalated cells.
Fig.37.5 ).Forexample,aGprotein–coupledH+ receptor(GPCR–GPR4)hasbeenlocalizedtothecollectingduct.ActivationofthisreceptorbyanincreaseinECF[H+]stimulatesH+ secretion.Alsointhecollectingduct,HCO3−-secretingintercalatedcells(B-orβ-ICs)expressabasolateralinsulin-relatedreceptor(IRR)thatisatyrosinekinase.ItisactivatedbyanincreaseinECF[HCO3−]andstimulatesHCO3− secretionbythecell.Asolubleadenylylcyclase(sAC)regulatedbyintracellularHCO3− appearstoalsoplayarollinregulatingcollectingductH+ secretion.Intheproximaltubule,basolateralmembranereceptortyrosinekinases(ErbB1andErbB2)sensechangesinECFPCO2.ActivationofthesereceptorsbyanincreaseinPCO2resultsingenerationofangiotensinII,whichactingfromthelumenviaAT-1Areceptors,stimulatesH+ secretion/HCO3− reabsorption.Alsointheproximaltubule,thenonreceptortyrosinekinase(Pyk2)sensesintracellular[H+].Whenitisactivatedbyanincreaseinintracellular[H+],H+ secretion/HCO3− reabsorptionisstimulated.Finally,thegatingofseveralionchannels(e.g.,therenaloutermedullaryK+ channel[ROMK])iseffectedbychangesineitherECForICFpH.Thesetoohavethepotentialtoserveascellularacid-basesensors.
Although some of the effects just described may be attributable directly to acidosis, many of these changes in cellular H+ transport are mediated by hormones or other factors. Three known mediators of the renal response to acidosis are endothelin, cortisol, and angiotensin II. Endothelin (ET-1)
Intheproximaltubule,metabolicacidosisincreasesthetransportkineticsoftheNa+/H+ antiporter(NHE3)andincreasesapicalmembraneexpressionoftheNa+/H+ antiporter,H+-ATPase,andthebasolateralNa+/3HCO3− symporter(NBCe1).Inthecollectingduct,acidosisleadstoexocyticinsertionofH+-ATPaseintotheapicalmembraneofintercalatedcells.Withlong-termacidosistheabundanceofkeyacid-basetransportersisincreasedintheproximaltubule(NHE3andNBCe1)andincollectingductintercalatedcells(H+-ATPaseandAE1).Lastly,acidosisdecreasesexpressionoftheCl−/HCO3− antiporterpendrininHCO3−-secretingintercalatedcells.