TY - JOUR
T1 - Atorvastatin does not ameliorate nephrogenic diabetes insipidus induced by lithium or potassium depletion in mice
AU - Markussen, Maria Linaa
AU - Jensen, Camilla Grønkjær
AU - Iervolino, Anna
AU - Rej, Soham
AU - Trepiccione, Francesco
AU - Christensen, Birgitte Mønster
PY - 2021
Y1 - 2021
N2 - 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
c1l). Biotinylation assays showed that acute (1hr) atorvastatin, simvastatin, or fluvastatin increased AQP2 membrane accumulation in mCCD
c1l cells showing that the cell line responds to acute statin treatment. To see whether chronic statin treatment abolish the Li effects, mCCD
c1l 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.
AB - 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
c1l). Biotinylation assays showed that acute (1hr) atorvastatin, simvastatin, or fluvastatin increased AQP2 membrane accumulation in mCCD
c1l cells showing that the cell line responds to acute statin treatment. To see whether chronic statin treatment abolish the Li effects, mCCD
c1l 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.
KW - AQP2
KW - NDI
KW - hypokalemia
KW - lithium
KW - statin
UR - http://www.scopus.com/inward/record.url?scp=85118995378&partnerID=8YFLogxK
U2 - 10.14814/phy2.15111
DO - 10.14814/phy2.15111
M3 - Journal article
C2 - 34762363
SN - 2051-817X
VL - 9
JO - Physiological Reports
JF - Physiological Reports
IS - 21
M1 - e15111
ER -