The nondipping blood pressure pattern induced by chronic intermittent hypoxia and its renal mechanism

Objective: Blood pressure (BP) typically decreases during sleep, known as the “dipping” pattern. A “nondipper”, characterized by <10% BP reduction during sleep, has an elevated cardiovascular risk. Intermittent hypoxia (IH) is used to model hypertension with sleep apnea, but its relation with BP dipping and its effect on the kidney remains unclear. Methods: Male C57BL/6J (WT) mice were exposed to either normoxia (NX) or IH (O 2 concentration reduced to 5% in 90 s every 3 min during 8 h within the light period, for >1 week). BP was measured by radiotelemetry, and the dipping state was assessed by comparing mean BP (MBP) between light and dark periods. High- or low-salt diet (8% or 0.05% NaCl) and Slc12a3 −/− mice (NCC-KO) were used to clarify the role of renal mechanism in the IH model mice. Results: WT mice exhibited a dipping BP pattern under NX, but showed a nondipping pattern under chronic IH. Low-salt diet restored the dipping pattern and high-salt diet reinduced the nondipping one in the IH-model mice. Chronic IH increased the phosphorylation of Na–Cl cotransporter (NCC) and Na–K–Cl cotransporter (NKCC2) in the kidney, without affecting ENaCα cleavage. Even NCC-KO mice showed a dipping pattern of BP under NX, which shifted to a nondipping pattern under chronic IH. As expected, treatment with furosemide restored the dipping pattern in NCC-KO mice under chronic IH. Conclusions: Chronic IH disrupts the physiological dipping pattern of BP through NCC and NKCC2 activation. This study underscores the kidney's role in the pathophysiology of nondippers with sleep apnea.