CFTR knock-out mice exhibit impaired renal compensation to dietary NaCl depletion

People with cystic fibrosis (CF) are at increased risk for fluid and electrolyte imbalances due to continuous salt loss. Here we study if renal CFTR dysfunction can contribute to salt-wasting in CF. Mice do not sweat and hence a CFTR KO mouse model was applied.

To explore sweat-independent mechanisms contributing to salt-wasting in CF, we NaCl-depleted CFTR KO and WT mice for 7 days. Thereafter, the renal adaptation, systemic electrolyte and acid-base homeostasis, plasma aldosterone and urine sodium excretion were assessed. Eventually, we also studied the pendrin KO mouse, knowing that CFTR is a crucial molecular modulator of pendrin function.

In CF mice, 7 days of NaCl depletion caused lower plasma Na⁺, K⁺, and Cl^- levels while HCO₃^- and aldosterone levels were increased. Interestingly, CF mice failed to increase renal pendrin protein abundance. Full loss of pendrin, as seen in pendrin KO mice, caused severe hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis during NaCl depletion. Interestingly, CF mice also exhibited decreased thick ascending limb and distal convoluted tubule function as seen in decreased NKCC2 and NCC phosphorylation.

CF mice have an impaired ability to retain salt and fluid when NaCl-depleted. This is likely caused by abnormal/absent renal tubulular CFTR activity which compromises renal adaptation in the thick ascending limb, distal convoluted tubule and collecting duct β-intercalated cells.