Amiloride restores renal medullary osmolytes in lithium-induced nephrogenic diabetes insipidus

In lithium-induced nephrogenic diabetes insipidus (NDI), alterations in renal medullary osmolyte concentrations have been assumed but never investigated. Amiloride can modify lithium-induced NDI, but the impact of amiloride in lithium-induced NDI on renal medullary osmolytes, aquaporins, and urea transporters is unknown and is the basis of this study. Rats fed lithium (60 mmol/kg dry food) over 4 wk developed NDI. Urine osmolality fell to 287 +/- 19 mosmol/kgH(2)O (controls 1,211 +/- 90 mosmol/kgH(2)O). Organic osmolytes in the renal medulla showed significant decreases compared with controls [inositol 221 +/- 35 to 85 +/- 10 mmol/ kg protein; sorbitol 35 +/- 9 to 3 +/- 1 mmol/ kg protein; glycerophosphorylcholine (GPC) 352 +/- 80 to 91 +/- 20 mmol/ kg protein; and glycine betaine 69 +/- 11 to 38 +/- 38 mmol/ kg protein]. Medullary urea content fell from 2,868 +/- 624 to 480 +/- 117 mmol/ kg protein. Concurrent administration of amiloride (0.2 mmol/l) in the drinking water restored urine osmolality (1,132 +/- 154 mosmol/kgH(2)O), and reduced urine volume. Medullary osmolyte content were restored to control values (inositol, 232 +/- 12; sorbitol 32 +/- 6; GPC, 244 +/- 26; glycine betaine, 84 +/- 5 mmol/ kg protein). Medullary urea rose to 2,122 +/- 305 mmol/ kg protein. Reduced AQP2, AQP3, and urea transporter (UT-A1) expression was significantly reversed following amiloride therapy. Data presented here provide further understanding of how amiloride may substantially restore the lithium-induced impaired renal concentrating mechanism.