Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats.

Abstract

A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of 18-arginineivasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study to clarify the mechanism by which Li administered orally for several weeks induces polyuria and NDI in rats. Albino rats consuming a diet which contained Li (60 mmol/kg) for 4 wk developed marked polyuria and polydipsia; at the end of 4 wk the plasma Li was 0.7±0.09 mM (mean±SEM; n = 36). Litreated rats had a significantly decreased (-33%) tissue osmolality in papilla and greatly reduced cortico-papillary gradient of urea (cortex-43%; medulla-64%; papilla-74%). Plasma urea was significantly (P < 0.001) lower in Li-treated rats (5.4±0.2 mM) compared with controls (6.8±03 mM). Medullary collecting tubules (MCT) and papillary collecting ducts (PCD) microdissected from Li-treated animals had higher content of protein than MCT and PCD from the control rats. The cAMP accumulation in response to AVP added in vitro was significantly (A = -60%) reduced. Also, the cAMP accumulation in MCIr and PCD after incubation with forskolin was markedly lower in Li-treated rats. Addition of 0.5 mM 1-methyl,3-isobutyl-xanthine did not restore the cAMP accumulation in response to AVP and forskolin in MCT from Litreated animals. In collecting tubule segments from polyuric rats with hypothalamic diabetes insipidus (Brattleboro homozygotes) the AVP-dependent cAMP accumulation was not diminished. The activity of adenylate cyclase (AdC) in MCT of Li-treated rats, both the basal and the activity stimulated by AVP, forskolin, or fluoride, was significantly (A --30%) reduced, while the activity of cAMP phosphodiesterase (cAMP- PDIE) in the same segment showed no significant difference from the controls. Also, the content of ATP in MCT microdissected from Li-treated rats and incubated in vitro did not differ from controls. The rate of ['4Cjsuccinate oxidation to '4CO2 in MAL was inhibited (-77%) by 1 mM furosemide, which indicates that this metabolic process is coupled with NaCl cotransport in MAL. The rate of "4CO2 production from I'4Cisuccinate in MAL was not significantly different between control and Li-treated rats. In MCT of control rats, the rate of I'4Cisuccinate oxidation was -3 times lower than in MAL.The rate of '4CO2 production from I'4Cjsuccinate in MCT of Li-treated rats was significantly (A +33%) higher than in MCT dissected from control rats. Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCI' and PCD to generate and accumulate cAMP in response to stimulation by AVPl, this defect is primarily due...

Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex.

“…Although the mechanisms by which hypokalemia causes nephrogenic diabetes insipidus are a matter of contention, it appears to be due to a reduction in the production of cAMP (the second messenger for vasopressin action) in response to vasopressin, either by direct inhibition of adenylate cyclase (2,16,25) or via increased prostaglandin production (14). Our previous observation that lithium causes a decrease in AQP2 expression could also be explained by this mechanism, as the lithium-induced polyuria is thought to be due to an inhibition of adenylate cyclase (26,27). This would suggest that the modulatory effect of vasopressin on AQP2 expression is mediated via the same (V 2 ) receptors that mediate the acute antidiuretic response.…”

Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla.

“…NDI and reduced expression ofAQP2. It is well established that lithium often causes a vasopressin-resistant urinary concentrating defect, i.e., NDI (2,3), associated with structural changes in the medullary collecting ducts (22) and that the rat provides a useful animal model of this (5,23 Figure 6. Immunoblots comparing AQP2 expression in inner medulla of lithium-treated rats (L) with (a) lithium-treated rats either thirsted for 48 h (T) or (b) infused with dDAVP for 7 d (V).…”

“…It has been suggested that lithium acts by inhibiting adenylate cyclase activity in the collecting duct principal cells (2,5), thus preventing the production of cAMP, the second messenger for vasopressin. Prostaglandins may (6) or may not (7) play a part in this inhibition.…”

Diabetes Insipidus: A Review

“…While lithium usually causes impaired urine concentration, only about 15% of patients taking lithium for >15 years develop full-blown NDI [74,82]. Lithium's mechanism in causing NDI is unknown and a variety of mechanisms have been proposed -one of which is by decreasing cellular cAMP, causing decreased insertion of AQP2 into the apical membrane [83,84]. Other research shows that lithium's action is likely not due to cAMP, but rather, to AQP2 transcription reduction and AQP2 mRNA degradation [85].…”