The aim of the experiments reported in the present work was: first, to generate a rat model of lithium-induced nephrogenic diabetes insipidus (NDI), and, second, to use this to test the hypothesis that the effects of lithium were far more reaching than merely the inhibition of vasopressin induced translocation and synthesis of the water channel protein AQP2. Specifically, the effect of lithium on the abundance and distribution of the other water channel proteins, AQP1, AQP3 and AQP4 was investigated. It was found that AQP3 protein abundance was significantly reduced in the renal medulla while AQP4 was not affected. In addition, it was further hypothesized that, given the known effects of lithium on the urea transporter UT-A1 and on sodium channels and transporters, the renal medullary osmotic gradient would be dissipated by lithium. This was examined indirectly by determining the amounts of organic osmolytes in the renal medulla of rats with lithium-induced NDI. Myo-inositol was found to be 85 � 9 mmol kg⁻1 protein in the NDI rats, a reduction of 38% compared with control values, sotbitol fell from 35� 9 mmol kg⁻� in the control rats to 2.5 � 0.5 mmol kg⁻�, and glycerophosphorylcholine levels in the experimental animals were 91 � 18 mmol kg⁻� protein compared with 372 � 72 mmol kg⁻� in the controls. In addition, betaine decreased to 38 � 2 mmol kg⁻� protein from 69 � 10 mmol kg⁻� protein in the control. The urea content of the medulla was found to have fallen from 2868 � 558 mmol kg⁻� protein to 480 � 105 mmol kg⁻� protein. These data indicated that indeed the medullary osmotic gradient, the driving force for AVP-dependent fluid reabsorption in the kidney was greatly reduced during lithium-induced NDI.
Thirdly, it was proposed that the sodium-channel blocker, amiloride, by acting to prevent lithium entry into the cells of the collecting duct, should ameliorate or abolish the adverse effects of lithium on the kidney. Treatment of rats with established NDI, with amiloride, reversed to a large extent the reduction in aquaporin protein expression and re-established the medullary osmotic gradient, as assessed by the ability of treated rats to concentrate their urine, and by the rise in amounts of medullary osmolytes. Administration of 0.5 mmol l⁻� amiloride to lithium-treated rats led to medullary AQP2 and AQP3 protein abundance increasing by 82% � 16% and 110% � 4% of the control level respectively. The content of urea in the medulla also increased to 2474 � 557 mmol kg⁻� protein.
Finally, since in humans it is known that the chronic effect of lithium on the kidney is to cause cortical fibrosis and renal failure, microarray studies were commenced to look for evidence of early changes in gene activity in response to lithium-administration. The results showed that 77 genes were either up- or down-regulated, in particular, genes that are involved in the apoptosis pathway.
In the light of these results it is plausible to suggest that the acute renal effects of lithium to induce NDI can be effectively mitigated, and reversed, by administration of amiloride. Whether this can serve to offset the chronic effects of lithium on the kidney awaits further investigation.
| Identifer | oai:union.ndltd.org:ADTP/201528 |
| Date | January 2008 |
| Creators | Jing, Yu, n/a |
| Publisher | University of Otago. Department of Physiology |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Yu Jing |
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