Nephron segment-specific inhibition of Na+/K+-ATPase activity by cyclosporin A

Abstract

Decreased kaliuresis and hyperkalemia are common complications of cyclosporin A (CsA) therapy. If CsA significantly inhibits renal tubular Na+/K(+)-ATPase activity, the alteration in transepithelial K+ secretion and K+ homeostasis could result in hyperkalemia. To investigate this possibility, we tested the effects of CsA on Na+/K(+)-ATPase activity in microdissected rat tubules. CsA, at a "toxic" concentration of 600 ng/ml, significantly inhibited Na+/K(+)-ATPase in cortical collecting ducts (CCD), medullary thick ascending limbs (mTAL), and outer medullary collecting ducts from the outer stripe (OMCDos) by 35%, 53%, and 39%, respectively. Cremophore, the commercial vehicle for CsA, did not change Na+/K(+)-ATPase activity in any nephron segment tested. To determine whether CsA inhibits Na+/K(+)-ATPase activity in a dose-dependent manner, microdissected CCD's were incubated with 300, 600, and 2500 ng/ml of CsA for 30 minutes. Na+/K(+)-ATPase activity was inhibited at 600 and 2500 mg/ml, but not at 300 ng/ml. No further inhibition of enzyme activity was noted at 2500 ng/ml. CsA did not change Na+/K(+)-ATPase activity in proximal tubule S1, S2, and S3 subsegments; cortical thick ascending limbs (cTAL), connecting tubules (CNT), or outer medullary collecting ducts from the inner stripe (OMCDis). Prolonging the incubation of CsA with S2 subsegments to 60 minutes did not result in inhibition of Na+/K(+)-ATPase activity. Ouabain-insensitive ATPase activity was unaffected by CsA or its vehicle in any nephron segment tested. In summary, CsA specifically inhibits Na+/K(+)-ATPase activity in the CCD, mTAL, and OMCDos.(ABSTRACT TRUNCATED AT 250 WORDS)