NH4+ absorption by the medullary thick ascending limb (MTAL) of Henle's loop, which causes the accumulation of NH4+/NH3 in the medullary interstitium, is a key step in the renal handling of ammonia. Accumulation of NH4+/NH3 in the medullary interstitium is necessary to the secretion of ammonia in the medullary collecting ducts and then to NH4+ excretion in the urine. The MTAL apical Na(+)-K+(NH4+)-2Cl- cotransporter BSC1/NKCC2 is responsible for the majority of the MTAL luminal NH4+ uptake. Stimulation of BSC1 expression by metabolic acidosis accounts for the increase of the MTAL ability to absorb NH4+ during this condition. Metabolic acidosis increases the mRNA and protein abudance and the transport activity of BSC1. Two factors have been demonstrated to mediate the effects of acidosis, an acid pH and glucocorticoids whose production augments during metabolic acidosis. These two factors thus control in a coordinated manner ammoniagenesis in the proximal tubule and MTAL NH4+ transport to ensure urinary acid excretion rates appropriate to the acid-base status.