Induced Pan‐nephron Mineralocorticoid Receptor Knockout Causes Na + Wasting and K + Retention

The mineralocorticoid receptor (MR) plays a key role in Na + and K + homeostasis. Constitutive MR deletion is lethal, but deletion along the connecting tubule (CNT) and collecting duct (CD) has relatively mild effects. To determine if this difference reflects MR actions along other nephron segments, we deleted MR along the entire nephron. Using the doxycyline‐inducible Pax8‐rtTA system, we deleted MR in the nephron of adult mice; RT‐PCR confirmed substantial mRNA reduction. MR knockout (MR KO) mice survived, but displayed weight loss, mild hyperkalemia, Na + wasting, and elevated plasma aldosterone at baseline. Although the abundance of ENaC was not affected, total and phosphorylated NCC (pNCC) abundance were slightly reduced. Low Na + diet (0.02% Na + ) enhanced the Na + ‐wasting phenotype with dramatic weight loss, hyponatremia, and severe hyperkalemia (6.57 mM). Although Na + deprivation increased pNCC in WT, it strikingly reduced pNCC in MR KO. In contrast, Na + deprivation did not affect β ENaC in WT, but increased it in MR KO. High K + diet (5% K + ) also produced weight loss, hyponatremia, and hyperkalemia (7.58 mM) with increased β ENaC abundance and decreased pNCC abundance in MR KO. It also produced significantly more volume contraction (Δ Hct) in MR KO than in WT. Induced pan‐nephron MR KO mice display a more severe phenotype than CNT/CD MR KO, but a less dramatic one than constitutive total body KO. Though unchanged at baseline, increased β ENaC abundance following diet changes likely reflects MR‐independent regulation; the phenotype suggests that MR is required for activation, not synthesis. Plasma K + appears to drive changes in NCC. Thus, baseline reductions of NCC in MR KO appear to be secondary to hyperkalemia, rather than direct MR effects in the DCT.