Abstract
Earlier we reported that the recombinant soluble (pro) renin receptor sPRR‐His upregulates renal aquoporin‐2 (AQP2) expression, and attenuates polyuria associated with nephrogenic diabetes insipidus (NDI) induced by vasopressin type 2 receptor (V2R) antagonism. Patients that receive lithium therapy develop polyuria associated NDI that might be secondary to downregulation of renal AQP2. We hypothesized that sPRR‐His attenuates indices of NDI associated with lithium treatment. Eight‐week‐old male C57/BL6 mice consumed chow supplemented with LiCl (40 mmol/kg diets) for 14 days. For the last 7 days mice received either sPRR‐His [30 μg/(kg day), i.v.; sPRR] or vehicle (Veh) via minipump. Control (Con) mice consumed standard chow for 14 days. Compared to Con mice, 14‐d LiCl treatment elevated water intake and urine volume, and decreased urine osmolality, regardless of sPRR‐His or Veh administration. These data indicate that sPRR‐His treatment does not attenuate indices of NDI evoked by lithium. Unexpectedly, epididymal fat mass was lower, adipocyte UCP1 mRNA and protein expression were higher, and multilocular lipid morphology was enhanced, in LiCl‐fed mice treated with sPRR‐His versus vehicle. The beiging of white adipose tissue is a novel metabolic benefit of manipulating the sPRR in the context of lithium‐induced NDI.
Highlights
Lithium is a metallic monovalent cation that has been used for >150 years as a simple and effective treatment for psychiatric illnesses and Alzheimer’s disease (Khanna 2006)
Mice were randomized into three groups that received 14 day treatment of either: (1) standard laboratory chow + no infusion; (2) LiCl (40 mmol/kg diets) + vehicle infusion (i.v.) for the last 7 days; or (3) LiCl [as in (2)] + with soluble form of PRR (sPRR)-His infusion (30 lg/(kg day), i.v.) for the last 7 days. sPRR-His was administered via osmotic minipump and this dose and duration is sufficient to upregulate renal AQP2 expression and prevent indices of nephrogenic diabetes insipidus (NDI) evoked by vasopressin type 2 receptor (V2R) antagonism in mice (Lu et al 2016)
24-h urine collection on day 14 indicated that sPRR excretion was elevated in sPRR-His treated mice versus the control and vehicletreated animals (Fig. 1A)
Summary
Lithium is a metallic monovalent cation that has been used for >150 years as a simple and effective treatment for psychiatric illnesses and Alzheimer’s disease (Khanna 2006). Despite its proven efficacy and affordability, lithium use has diminished over the past several decades due to adverse off-target side effects that include nephrotoxicity (Nielsen et al 2008b; Walker 1993). In this regard, ~70% of patients that receive lithium therapy develop nephrogenic diabetes insipidus (NDI) characterized by polyuria, polydipsia, and reduced urine osmolality due to impaired urine concentrating capability (Bedford et al 2003; Timmer and Sands 1999). At present no effective therapy exists to manage lithium-induced NDI
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