Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
Department of Translational Medical Sciences, University of Campania "L. Vanvitelli", Naples, Italy.
Physiol Rep. 2021 Nov;9(21):e15111. doi: 10.14814/phy2.15111.
Acquired forms of nephrogenic diabetes insipidus (NDI) include lithium (Li)-induced and hypokalemia-induced NDI. Both forms are associated with AQP2 downregulation and collecting duct (CD) cellular remodeling. Statins are cholesterol-lowering drugs appearing to increase AQP2 membrane-translocation and improve urine concentration in other NDI models. We have investigated if statins are able to prevent or rescue the Li-induced changes in mice and in a mouse cortical CD cell line (mCCD ). Biotinylation assays showed that acute (1hr) atorvastatin, simvastatin, or fluvastatin increased AQP2 membrane accumulation in mCCD cells showing that the cell line responds to acute statin treatment. To see whether chronic statin treatment abolish the Li effects, mCCD cells were treated with 48 h Li, combined Li/atorvastatin or combined Li/simvastatin. Li reduced AQP2, but combined Li/atorvastatin or Li/simvastatin did not prevent AQP2 downregulation. In mice, chronic (21 days) Li increased urine output and reduced urine osmolality, but combined Li/atorvastatin did not prevent these effects. In inner medulla (IM), Li reduced total AQP2 and increased pS261-AQP2. Combined Li/atorvastatin did not abolish these changes. Atorvastatin did not prevent a Li-induced increase in intercalated cells and proliferation in IM. In mice with already established NDI, atorvastatin had no effect on the Li-induced changes either. Mice subjected to 14 days of potassium-deficient diet developed polyuria and AQP2 downregulation in IM. Co-treatment with atorvastatin did not prevent this. In conclusion, atorvastatin does not appear to be able to prevent or rescue Li-NDI or to prevent hypokalemic-induced NDI.
获得性肾性尿崩症（NDI）包括锂（Li）诱导和低钾血症诱导的 NDI。这两种形式都与 AQP2 下调和集合管（CD）细胞重塑有关。他汀类药物是一种降低胆固醇的药物，似乎能增加 AQP2 的膜转位，并改善其他 NDI 模型中的尿液浓缩。我们研究了他汀类药物是否能够预防或挽救锂诱导的小鼠和小鼠皮质 CD 细胞系（mCCD）的变化。生物素化测定表明，阿托伐他汀、辛伐他汀或氟伐他汀在 mCCD 细胞中急性（1 小时）处理可增加 AQP2 膜积聚，表明该细胞系对急性他汀类药物治疗有反应。为了观察慢性他汀类药物治疗是否能消除 Li 的影响，用 48 小时 Li、Li/阿托伐他汀或 Li/辛伐他汀联合处理 mCCD 细胞。Li 降低了 AQP2，但 Li/阿托伐他汀或 Li/辛伐他汀联合处理不能预防 AQP2 的下调。在小鼠中，慢性（21 天）Li 增加了尿量并降低了尿渗透压，但 Li/阿托伐他汀联合处理不能预防这些变化。在内髓质（IM）中，Li 降低了总 AQP2 并增加了 pS261-AQP2。Li/阿托伐他汀联合处理不能消除这些变化。阿托伐他汀不能预防 Li 诱导的 IM 中闰细胞增加和增殖。在已经建立的 NDI 小鼠中，阿托伐他汀对 Li 诱导的变化也没有影响。接受 14 天低钾饮食的小鼠出现多尿和 IM 中 AQP2 下调。阿托伐他汀联合治疗不能预防这种情况。总之，阿托伐他汀似乎不能预防或挽救 Li-NDI 或预防低钾诱导的 NDI。
