conclusions: The roles of the Na /HCO cotransporters NBCn1 and NBCn2 as well as their activators IRBIT and L-IRBIT in the regulation of the mTAL transport of NH , HCO , and NaCl are investigated. Dietary challenges of NH Cl, NaHCO or NaCl all increase the abundance of NBCn1 and NBCn2 in the outer medulla. The three challenges generally produce parallel increases in the abundance of IRBIT and L-IRBIT in the outer medulla. Both IRBIT and L-IRBIT powerfully stimulate the activities of the mTAL isoforms of NBCn1 and NBCn2 as expressed in Xenopus oocytes. Our findings support the hypothesis that NBCn1, NBCn2, IRBIT and L-IRBIT appropriately promote NH shunting but oppose HCO and NaCl reabsorption in the mTAL, and thus are at the nexus of the regulation pathways for multiple renal transport processes. unassigned: The medullary thick ascending limb (mTAL) plays a key role in urinary acid and NaCl excretion. NBCn1 and NBCn2 are present in the basolateral mTAL, where NBCn1 promotes NH shunting. IRBIT and L-IRBIT (the IRBITs) are two powerful activators of certain acid-base transporters. Here we use western blotting and immunofluorescence to examine the effects of multiple acid-base and electrolyte disturbances on expression of NBCn1, NBCn2 and the IRBITs in rat kidney. We also use electrophysiology to examine the functional effects of IRBITs on NBCn1 and NBCn2 in Xenopus oocytes. NH Cl-induced metabolic acidosis (MAc) substantially increases protein expression of NBCn1 and NBCn2 in the outer medulla (OM) of rat kidney. Surprisingly, NaHCO -induced metabolic alkalosis (MAlk) and high-salt diet (HSD) also increase expression of NBCn1 and NBCn2 (effect of NaHCO ?>?HSD). Moreover, all three challenges generally increase OM expression of the IRBITs. In Xenopus oocytes, the IRBITs substantially increase the activities of NBCn1 and NBCn2. We propose that upregulation of basolateral NBCn1 and NBCn2 plus the IRBITs in the mTAL: (1) promotes NH shunting by increasing basolateral HCO uptake to neutralize apical NH uptake during MAc; (2) inhibits HCO reabsorption during MAlk by opposing HCO efflux via the basolateral anion exchanger AE2; and (3) inhibits NaCl reabsorption by mediating (with AE2) net NaCl backflux into the mTAL cell during HSD. Thus, NBCn1, NBCn2 and the IRBITs are at the nexus of the regulatory pathways for multiple renal transport processes.