Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression.
Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg2+ channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.
da Silva
Cristianne Alexandre
CA
Laboratório de Pesquisa Básica LIM-12, Faculdade de Medicina da USP, Av. Dr. Arnaldo 455, Sala 3310, CEP 01246-903, São Paulo, Brazil.
de Bragança
Ana Carolina
AC
Shimizu
Maria Heloísa Massola
MH
Sanches
Talita Rojas
TR
Fortes
Maria Angela Zanella
MA
Giorgi
Ricardo Rodrigues
RR
Andrade
Lúcia
L
Seguro
Antonio Carlos
AC
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007008:Hypokalemia / Q000139:chemically induced / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000097:blood; D007668:Kidney / Q000378:metabolism; D007677:Kidney Function Tests; D008274:Magnesium / Q000097:blood / Q000652:urine; D008297:Male; D011141:Polyuria / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D020123:Sirolimus / Q000009:adverse effects* / Q000097:blood; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D050053:TRPM Cation Channels / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014867:Water / Q000378:metabolism
C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D050053:TRPM Cation Channels; C507531:TRPM6 protein, rat; D045162:Thiazolidinediones; D014867:Water; D000077154:Rosiglitazone; D012964:Sodium; D008274:Magnesium; D020123:Sirolimus