CHRONIC HYPEROSMOLALITY INCREASES NHE3 ACTIVITY IN OKP CELLS

This study investigated the effect of chronic hypertonicity on the OKP cell Na/H antiporter, encoded by Na/H exchanger 3 (NHE3), Chronic (48 h) increases in extracellular glucose, mannitol, or raffinose concent ration caused a significant increase in Na/H antiporter activity, whil e increases in urea concentration were without effect, This effect was seen with changes in osmolality of only 20 mOsm/liter, a magnitude th at is observed clinically in poorly controlled diabetes mellitus, Incr eases in mannitol concentration acutely inhibited and chronically stim ulated Na/H antiporter activity, The increase in Na/H antiporter activ ity induced by hypertonic incubation was resistant to 10(-7) and 5 x 1 0(-6) M but inhibited by 10(-4) M ethylisopropyl amiloride, consistent with regulation of NHE3. In addition, hypertonicity increased total c ellular and plasma membrane NHE3 protein abundance twofold, with only a small increase in NHE3 mRNA abundance, We conclude that chronic path ophysiologically relevant increases in tonicity lead to increases in N HE3 protein abundance and activity, This may be responsible for increa sed proximal tubule apical membrane Na/H antiporter activity in poorly controlled diabetes mellitus, which could then contribute to hyperten sion, glomerular hyperfiltration and diabetic nephropathy.