AbstractsBiology & Animal Science

Lithium is a common therapeutic treatment for bipolar disorder. Although it is an effective therapeutic agent, lithium has a number of significant side effects, of which the renal manifestations are the most important. The renal side effects of lithium fall into 3 main categories: nephrogenic diabetes insipidus (NDI) (severe diminution of the ability to concentrate the urine), chronic kidney disease which manifests as a slowly progressive chronic interstitial fibrosis, and acute lithium intoxication. Fifty percent of the patients on lithium, experience to some degree, a loss of the ability to concentrate the urine, and although less well documented, lithium also causes chronic interstitial fibrosis in some patients. The mechanism of action of lithium on the kidney has been a subject of ongoing research. In conjunction with these studies, amiloride has been shown to reduce some of the renal side effects of lithium, but the mechanisms behind how amiloride modifies lithium-induced injury remain unknown. It is well known that lithium entry into the principal cells of the collecting duct occurs by way of the epithelial sodium channel (ENaC). The principle action of amiloride, a known blocker of ENaC is to prevent the entry of lithium into the cells. Amiloride is well known to reduce the manifestation of NDI in the short term. However, the long-term effects of amiloride on lithium-induced renal injury are unknown. This thesis set out to examine some of the renal functional and molecular responses associated with amiloride administration in lithium-induced renal injury. Amiloride has been shown to partially attenuate lithium-induced NDI on a short-term basis and hence, the aim of the work reported here was to examine the long-term effects of amiloride on lithium-induced kidney injury. Renal functional parameters, as well as the expression of the renal transporter aquaporin 2 (AQP2) after one month of lithium treatment were investigated (Chapter 3). The experimental data confirmed that lithium treatment induced NDI, associated with a decrease in AQP2 in the principal cells of the collecting ducts. In addition, the initial morphological changes in the cortical collecting ducts were verified. The renal picture after one month of lithium treatment was then used as a baseline, against which the effect of amiloride on the further progression of lithium-induced renal damage could be assessed. It has been previously shown that chronic lithium treatment; sufficient to maintain plasma levels at around 1 mmol l-1, regarded as an effective level in humans, induces interstitial fibrosis in the kidneys of experimental rats. Hence, the effect of amiloride on the progression of lithium-induced fibrosis was also examined. It was hypothesised that if the action of lithium were to cause the development of fibrotic foci in the kidney as a result of its entry into the principal cells of the collecting duct, then amiloride would prevent the progression of fibrosis in the kidney. The main finding of this study was that six months of lithium…