CELLULAR ADAPTATION OF THE RAT MEDULLARY THICK ASCENDING LIMB TO CHRONIC-RENAL-FAILURE

Chronic renal failure (CRF) is accompanied by adaptive changes in rena l and extrarrenal epithelial ionic transport. Fluid reabsorption in th e thick ascending limb of Henle is increased and the capacity to lower the urine osmolality in water diuresis is preserved. To study the cel lular mechanism of this adaptation, we measured intracellular cAMP in microdissected medullary thick ascending limb (mTAL) segments in rats with CRF. mTAL exhibited in CRF nephrons an increase of basal cAMP fro m 6.0 +/- 1.5 in controls to 47.0 +/- 10.3 fmol. mm(-1) tubule in CRF (P < 0.05). Maximally stimulated cAMP levels (10(-3) M IBMX plus 10(-5 ) M Forskolin) were different from basal levels in controls (6.0 +/- 1 .5 vs 63.1 +/- 18.8, P < 0.05) but not from basal levels in CRF (47.0 +/- 10.3 vs 63.0 +/- 16.0, P = N.S.). Preincubation with the adenylate cyclase inhibitor 2'5'-dideoxyadenosine (DDA) 10(-4) M produced no ch anges in cAMP in controls (93.7 +/- 10.3% of DDA untreated samples) wh ereas it decreased to 76.2 +/- 8.8% (24% inhibition) in CRF (P < 0.05) . No differences between controls and CRF groups were found in basal a nd stimulated cAMP in red blood cells and distal colon. The data would suggest that the cAMP pathway is an intracellular signal for mTAL ada ptation in epithelial transport and that the adenylate-cyclase system is specifically activated in CRF.