Importance of adenylyl cyclase 6 in developing lithium‐induced nephrogenic diabetes insipidus

Abstract

Nephrogenic diabetes insipidus (NDI) develops in approximately 50% of psychiatric patients being treated with lithium (Li+). The mechanism behind Li+‐induced NDI (Li‐NDI) is only poorly understood, but it occurs at least partly due to reduced aquaporin‐2 (AQP2) expression, leading to lower water reabsorption in collecting ducts (CD) of the kidney. A suggested mechanism inducing these effects is that Li+ inhibits adenylyl cyclase (AC) activity and thereby decreases cAMP levels and subsequently reduces AQP2 abundance and membrane targeting. In the present study, we tested the hypothesis that Li‐NDI would not develop in mice lacking AC6, the AC isoform responsible for the majority of vasopressin‐induced inner medullary (IM) cAMP formation. Total‐body AC6 knockout (AC6−/−) mice and newly developed connecting tubule/principal cell‐specific AC6 knockout mice (AC6loxloxCre) were studied. Similar to AC6−/− mice, the novel AC6loxloxCre mice had lower urine osmolality [mean ± SE (n): control 2363 ± 114 mmol/kg (17), AC6loxloxCre 1219 ± 49 mmol/kg (9); P < 0.05] and higher water intake [control 0.19 ± 0.01 g/g BW/24h (7), AC6loxloxCre 0.28 ± 0.02 g/g BW/24h (6); P < 0.05]. In both controls, AC6−/−, and in AC6loxloxCre mice, dietary Li+ administration increased the water intake (P < 0.05) and reduced the urine osmolality (P < 0.05). Similar to AC6−/− mice, the AC6loxloxCre mice showed under standard conditions lower medullary levels of AQP2 (42% reduction, P < 0.05) and pS256‐AQP2 and (51% reduction, P < 0.05) and the levels were further reduced by respectively 54% and 57% after Li+ administration (P < 0.05). Furthermore, Li+ induced an increase in the numbers of proliferating cell nuclear antigen‐positive cells in the IMCD in both AC6loxloxCre (~2200% increase, P < 0.05) and control mice (~2600% increase, P < 0.05). However, compared to control mice, a greater % of H+‐ATPase B1 subunit‐positive cells were found in the AC6loxloxCre mice under both standard condition (32%, P < 0.05) and after Li+‐administration (33%, P < 0.05). Collectively, AC6 plays a minor role in the development of Li‐NDI, but could have an important function in determining the intercalated‐to‐principal cell ratio, which is altered during Li‐NDI.Support or Funding InformationFunding to R.A.F. is provided by the Novo Nordisk Foundation, the Lundbeck Foundation and Danish Medical Research Council. T.R. is supported by NIDDK 1R01DK110621‐01, the O'Brien Center for Acute Kidney Injury Research Grant P30DK079337, the Diabetes Endocrinology Research Center P30DK063491, the AHA 15BGIA22410018 and Satellite Healthcare (a not‐for‐profit renal care provider).