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Sex-specific effects of LiCl treatment on preservation of renal function and extended life-span in murine… Hart, David A Jun 27, 2016

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REVIEW Open AccessSex-specific effects of LiCl treatment onpreservation of renal function andextended life-span in murine models ofSLE: perspective on insights into thepotential basis for survivorship in NZB/Wfemale miceDavid A. Hart1,2,3AbstractConsiderable research effort has been invested in attempting to understand immune dysregulation leading toautoimmunity and target organ damage. In systemic lupus erythematosus (SLE), patients can develop a systemicdisease with a number of organs involved. One of the major target organs is the kidney, but patients vary in theprogression of the end-organ targeting of this organ. Some patients develop glomerulonephritis only, while othersdevelop rapidly progressive end organ failure. In murine models of SLE, renal involvement can also occur. Studiesperformed over the past several years have indicated that treatment with LiCl of females, but not males of theNZB/W model, at an early age during the onset of disease, can prevent development of end-stage renal disease ina significant percentage of the animals. While on Li treatment, up to 80 % of the females can exhibit long-termsurvival with evidence of mild glomerulonephritis which does not progress to renal failure in spite of on-goingautoimmunity. Stopping the treatment led to a reactivation of the disease and renal failure. Li treatment of othermurine models of SLE was less effective and decreased survivorship in male BxSB mice, exhibited little effect onmale MRL-lpr mice, and only modestly improved survivorship in female MRL-lpr mice. This perspective piecediscusses the findings of several related studies which support the concept that protecting target organs such asthe kidney, even in the face of continued immune insults and some inflammation, can lead to prolonged survivalwith retention of organ function. Some possible mechanisms for the effectiveness of Li treatment in this contextare also discussed. However, the detailed mechanistic basis for the sex-specific effects of LiCl treatment particularlyin the NZB/W model remains to be elucidated. Elucidating such details may provide important clues fordevelopment of effective treatment for patients with SLE, ~90 % of which are females.Keywords: Murine SLE, Preventing renal failure, Lithium treatment, Sex differences, FemalesCorrespondence: hartd@ucalgary.ca1Department of Surgery, Wound Healing Initiative, McCaig Institute for Boneand Joint Health, University of Calgary, 3330 Hospital Drive NW, Calgary,Alberta T2N 4N1, Canada2Faculty of Kinesiology, University of Calgary, Calgary, Alberta, CanadaFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Hart Biology of Sex Differences  (2016) 7:31 DOI 10.1186/s13293-016-0085-7BackgroundIn autoimmune diseases, immune dysfunction can leadto the induction of autoantibodies and/or self-reactivelymphocytes such as T-lymphocytes (reviewed in [1, 2]).In some autoimmune diseases, such as myastheniagravis, the target of the autoantibodies are very specificfor particular tissues (reviewed in [3]), while in otherssuch as rheumatoid arthritis, several or a few joints canbe involved, but it is a systemic disease. Similarly, in sys-temic lupus erythematosus (SLE), a spectrum of auto-antibodies can be present and a number of target tissues(e.g., kidney, skin, other organs) may be involved (dis-cussed in [4–6]). As with many autoimmune diseases,the incidence of such diseases is much greater in femalesthan males, with the ratio in SLE being ~9 F/1 M(reviewed in [7]).With diseases such as SLE, it is clear that there is agenetic component to the disease (reviewed in [8]), aswell as some ethnic associations (reviewed in [9–12]),particularly with end-stage renal dysfunction. Thus,many African-Americans have serious progressive renalinvolvement compared to non-African-Americans.While patients with SLE can have a number of targettissues involved, the kidney is a major organ that is in-volved. However, in spite of a somewhat similar pattern ofautoantibodies being present, some patients can have verymodest glomerulonephritis (class I/II) which does not pro-gress while others can have severe renal involvementwhich progresses rapidly to tubulosclerosis and end-stagerenal failure (class III/IV) (discussed in [13, 14]). Detailsregarding the basis (e.g., genetics, immunological dysfunc-tion, target organ responsiveness) for such variation inrenal involvement remain to be elucidated. What is clearis that in some patients, the target tissue (e.g., kidney) issomewhat protected from end-stage damage, while inothers, this is not the case. Some of these differences inhuman disease appears to have a genetic basis with kid-ney-associated genes playing a role (reviewed in [15,16]). While considerable effort has gone into trying tounderstand the immune dysfunctions leading to renal in-volvement with many new treatments (discussed in [14]),our understanding of target organ resistance to immuneinsults is less well defined. However, murine models ofSLE can likely provide useful information regarding hu-man disease (reviewed in [17, 18]).Murine models of SLEThere are several mouse models of SLE available forstudy (reviewed in [19–21]). Some of these, such as theMRL-lpr or BxSB mice, have defined mutations thatcontribute to the autoimmune disease. For instance, inthe BxSB model, only males get the disease, and in theMRL-lpr mouse, the parent strain (e.g., MRL-n) has anumber of immune dysfunctions which contribute tothe development of the autoimmunity and includes ex-cessive lymphoproliferation in the liver and spleen(reviewed in [19, 20]; and discussed in [22]), factors notusually observed in patients with SLE. In contrast, in theNZB/W F1 model both parental strains contribute tothe SLE-like disease, and a number of genes are in-volved. Some of these relate to the immune dysfunctionswhich appear in the F1 mice, while others appear to berelated more to the target organ involvement. In thisNZB/W F1 model, females get a more rapid and pro-gressive disease with renal failure by ~10–12 months ofage, while the males get a much more mild disease anddo not start to experience overt renal failure until ~20+months of age (reviewed in [19, 20]). Thus, some sex-related factors (e.g., sex hormones; discussed in [23, 24])also appear to play a role in development and progres-sion of end-stage renal failure, possibly at the level ofsex hormones on immune activities. Therefore, whethersex hormone variables may be related to immune dys-function activities or some other factors related to thekidneys themselves is still not clear, but this point isrelevant to the discussion which follows. Interestingly,females of the NZB/W F1 combination gain significantweight as they age, often leading to weights that aredouble or more those of the parent strains [25, 26].Much of this weight is due to subcutaneous and intra-peritoneal fat deposition. Given parallels between targetorgan involvement, and the sex differences notedabove, the NZB/W F1 model was chosen for detailedinvestigation regarding treatments that could preventrenal failure and, thus, prolong the life-span ofanimals in the face of immune dysfunction andautoantibodies.Influence of lithium chloride treatment on diseaseprogression in male BxSB, female MRL-lpr, and femaleNZB/W miceBackgroundSalts of Li have been used extensively in the treatment ofbipolar disease since ~1949 when Cade reported that Litreatment of guinea pigs led to a calming effect [27]. Inter-estingly, low concentrations of Li salts are known to be acomponent of a number of springs touted as being benefi-cial for treating a variety of ailments. However, use is oftenassociated with side effects (reviewed in [28]).Another limitation of Li salts in the treatment of bipo-lar disease is that efficacious doses are close to toxicdoses, and thus, patients taking Li salts must be carefullymonitored and evaluated for side effects. As Li salts arenatural compounds, they cannot be patented as such, sothere is little incentive for industry to invest in their ap-plications. Li exists as two major isotopes, Li-6 and Li-7,and natural Li is ~95 % Li-7. This is relevant since theionic radius of Li-6 is similar to potassium, while thatHart Biology of Sex Differences  (2016) 7:31 Page 2 of 10for Li-7 is similar to Mg, and thus, the two isotopescould affect different ionic environments.Li salts are known to influence adenyl cyclase [29], theNaK membrane transporter [30], and the Wnt/beta-ca-tenin system (reviewed in [31]). While it has been verydifficult to identify normal functions of Li in animals, Lican impact a number of biological systems and thus canbe considered a regulator molecule (discussed in [32]).In a series of reports in the 1970s, 1980s, and early1990s, it was demonstrated that Li salts can influencelymphocyte and polymorphonuclear leukocyte (PMN)activities both in vitro and in vivo (reviewed in [32–34]).Therefore, it was possible that Li treatment could haveimmunomodulatory influences on immune processes.While not used in SLE per se, it has been noted thatpatients on Li salts who also had SLE sometimes experi-enced an exacerbation of their SLE, but this was not aconsistent finding (discussed in [32]).Studies of Li effects on survival in murine models of SLEInitial studies investigated the effect of 4 mg of LiCl/dayvia the intraperitoneal (IP) route on survival of youngmale BxSB mice, female MRL-lpr mice, and femaleNZB/W mice. Li treatment led to decreased survival inthe BxSB model [35], some modest enhancement of sur-vival in MRL-lpr female mice, depending on how earlythe Li treatment was initiated [22], and significant sur-vival of female NZB/W mice [25, 26].In the NZB/W model, survival was significantly pro-longed by >50 % when the female animals were started onLi treatment at 8–10 weeks of age, an age when the SLEwas detectable (e.g., autoantibodies in serum, early glom-erulonephritis) [25, 26]. This enhanced survival in a subsetof female NZB/W mice was a “cure” but was not a defini-tive cure as stopping Li treatment led to a reactivation ofrenal disease and subsequent accelerated death. Therefore,treatment with Li led to the transient resistance to ter-minal end-stage renal failure in a subset of female NZB/W mice with early disease. Why this particular subset offemale animals survived while on treatment, and othersremained susceptible to the autoimmune insults, was un-clear from these initial studies. However, histologic ana-lysis of kidneys from some survivors indicated that theyexpressed signs of continued glomerulonephritis but ap-parently failed to convert to tubule sclerosis which is crit-ical in the development of renal failure. In this regard,these survivors resembled some human SLE patients whohave evidence for glomerulonephritis class I/II which doesnot progress to tubule involvement and sclerosis. Relevantto the current discussion, female NZB/W mice on Li diddevelop polydipsia while being treated, so renal functionwas impacted in these mice. Interestingly, polydipsia de-veloped in all mice treated with Li salts, so this was notunique to survivors.Additional studies to further characterize theeffectiveness of LiCl treatment in NZB/W miceTiming of initiation of treatmentSubsequent studies indicated that there was an agedependence for the effectiveness of LiCl treatment infemale NZB/W mice. The optimal time to initiate treat-ment was found to be 6–8 weeks of age, when featuresof SLE were just beginning. Delaying initiation of treat-ment to 16 or 28 weeks of age led to a diminished num-ber (28–35 %) of long-term survivors [36]. It was alsofound that initiating treatment at a very early age of ~4 weeksof age did not further enhance survival over that observedat 6–8 weeks of age (~40 % at 4 weeks of age vs 50–60 %at 6–7 weeks of age) [36]. In fact, starting Li treatment at4 weeks of age actually led to a somewhat lower long-term survival rate. Thus, optimization of effectiveness ofLiCl treatment was potentially associated with events oc-curring between 4 and 6–7 weeks of age, with a ~60 %long-term survival rate. The most prominent event, withassociated secondary changes occurring in mice duringthis time frame, is likely the onset of puberty. Puberty inmice occurs at ~6 weeks of age (discussed in [37]). As thecells in the kidneys do express estrogen receptors(reviewed in [38]), they should be responsive to sex hor-mones. If this association between the onset of pubertyand optimal LiCl responsiveness is correct, the timing re-sults likely indicate that Li modulates puberty-associatedchanges in gene/protein expression/location in some man-ner, rather than prevents the expression of some tubule-associated gene/protein expression.Effect of isotope, dosage, timing, and route of exposure onLi effectivenessNatural Li exists as predominantly two isotopes, Li-7and Li-6 (discussed in [21, 32–34]). Natural Li is com-prised of ~95 % Li-7 and ~5 % Li-6. This point is poten-tially relevant to understanding the mechanism(s) of Liaction as Li-6 has an ionic radius similar to Na, whileLi-7 has an ionic radius more similar to Mg (discussedin [21, 32–34]). Therefore, Li-6 may affect NaK ATPasesmore readily than Li-7. In contrast, Li-7 may affect Mg-dependent systems more effectively (e.g., adenyl cyclase).Daily treatment of female NZB/W mice starting at~8 weeks of age with 4 mg Li-6 (95 %) or Li-7 (99 %)led to similar survival rates over the long term [25].Thus, these results did not provide additional insightsinto potential mechanistic effects of these Li isotopes.However, it was noted that Li-6 did induce more poly-dipsia that did Li-7 (Hart, unpublished observations).Administration of the LiCl via the drinking water was in-effective in promoting long-term survival of female NZB/W mice at doses that were not toxic [39]. Interestingly, Li-6in the drinking water was much more toxic than Li-7 at thehigher doses investigated [39]. Administration of the Li viaHart Biology of Sex Differences  (2016) 7:31 Page 3 of 10the IP route was only slightly effective when 2 mg/day wasused instead of 4 mg/day, as assessed by long-term survival[40]. Interestingly, administering 4 mg LiCl/day via the IProute was partially dependent on the time of day the Li wasadministered, with administration during the morningmore effective than the evening [40]. As mice are more ac-tive at night, and their adrenal steroid pulses are the reverseof humans (e.g., higher in the morning and lower in theafternoon), higher levels of glucocorticoids occur in theevening. Interestingly, administration of melatonin did notmimic the effectiveness of Li [40].Given that administration of 4 mg LiCl in the morningor evening was effective in protecting a subset of femaleNZB/W mice from end-stage renal failure, studies wereundertaken to treat a panel of 6–8-week-old femaleswith 4 mg LiCl in the morning and evening (a total of8 mg of Li/day). Animals were treated 7 days/week for18 months [41]. This treatment regimen led to the long-term survival of ~80 % of the mice to a time when100 % of the control mice had been dead for >7 months[41]. Again, these survivors exhibited some evidence ofglomerulonephritis, but no tubule sclerosis ([41], andunpublished observations). Furthermore, cessation of Litreatment at 18 months of age again led to a reactivationof the disease and subsequent death. Thus, even withthis more intense treatment regimen, one of the majortarget organs was only protected during treatment, andfollowing stoppage of treatment, the target organ wasagain apparently susceptible to immune insults. The im-pact of Li is a reversible phenomenon even after a pro-tracted treatment protocol. Thus, while on the LiCltreatment, the vast majority of the NZB/NZW femaleswere “cured” of the development of end-stage renal fail-ure, but this cure was conditional and not definitive.LiCl treatment does not enhance survival of male NZB/WmiceAs discussed above, male NZB/W mice exhibit a moremild disease course than females (reviewed in [19, 20]).The onset of the SLE is slower in males, and they live amuch longer life-span. Treatment of male NZB/W micewith 4 mg LiCl/day IP, 7 days per week starting at 8–10 weeks of age, did not influence survival out to nearly81 weeks of age, a time point when ~90 % of the un-treated controls had died [36]. Therefore, the diseasecourse must be somewhat different in the females wherethe SLE is more aggressive.The above findings with male NZB/NZW mice, andthe earlier discussion of the effectiveness of LiCl treat-ment increasing following onset of puberty, lead to thepossibility that androgens are protective against develop-ment of renal dysfunction and estrogens contribute tothe susceptibility of female NZB/NZW mice to renaldysfunction. Such conclusions are supported by theliterature, where it has been noted that castration ofmale NZB/NZW mice increases their susceptibility tosuch renal disease and ovariectomy of female mice leadsto a diminished susceptibility (reviewed in [19, 20]).Thus, future studies assessing the LiCl responsiveness ofcastrated males and ovariectomized females could pro-vide further clues to the renal mechanisms responsiblefor responsiveness. Of particular interest would be com-parison studies with NZB/NZW mice castrated or ovari-ectomized prior to onset of puberty or after pubertyonset.LiCl treatment does not overtly alter autoantibody profilesin female NZB/W miceAs discussed above, Li ions have been reported to exertsome immunomodulatory effects (discussed in [21, 32–34]).To investigate whether Li treatment of female NZB/Wmice led to overt immunosuppression, serum from treatedand untreated mice were analyzed for autoantibodies,antibodies to porcine renal tubule cell lysates [42], andRNA from treated and untreated mouse kidneys wereassessed for TNF transcripts [43].To assess the effect of Li treatment on autoantibodies,female NZB/W mice were started on 4 mg Li-7 at8 weeks of age. Serum levels for anti-single strandedDNA and anti-gp70 were not significantly different be-tween treated and untreated mice at 16, 22, and 28 weeksof age (prior to renal failure). Western blotting analysisof serum reactivity to porcine renal tubule lysates fromtreated and untreated mice also did not reveal anygroup-specific differences, although some individual dif-ferences were noted within both groups [42]. Similarly,messenger RNA (mRNA) levels for the proinflammatorycytokine, TNF-alpha, were similar in extracts of totalkidneys of treated and untreated mice at 28 weeks of age[43]. While the analysis was not extensive, and did notevaluate a large number of autoantibodies or cytokines,no evidence for an overt immune effect of Li treatmentwas detected. However, it is clear that technologies havechanged since these studies were performed and the ap-proach should be revisited to gain a more complete per-spective regarding Li effects on immune parameters.Influence of Li treatment on gene expression in the kidneyAs mentioned above, mRNA levels for TNF-alpha werenot inhibited by Li treatment in kidneys of Li-treated fe-male mice. Additional analysis also revealed that expres-sion of gp70, a reported nephritogenic stimulus [44] infemale NZB/W mice, was not inhibited by Li-treatmentat 16, 22, and 28 weeks of age [43]. In fact, at 22 weeksof age, mRNA levels for gp70 were significantly elevatedin Li-treated mice.Interestingly, mRNA levels for the plasminogen activa-tor, urokinase, were significantly elevated at 16 (p < 0.01),Hart Biology of Sex Differences  (2016) 7:31 Page 4 of 1022 (p < 0.00001), and 28 (p < 0.01) weeks of age. As uro-kinase is produced by tubule epithelial cells (reviewed in[45]), and expression could interfere with fibrin depositionand development of tubule sclerosis (discussed in [43]),this finding may be relevant to the mechanism of Li ac-tion. However, in vivo, it may be more complicated thanthat interpretation since elevations in urokinase mRNAlevels were somewhat uniformly elevated in mice at thoseages, but earlier studies had indicated only about 50 % ofthe mice would be long-term survivors [25]. Therefore, el-evated urokinase mRNA levels were associated with Litreatment, but that association was likely not a completeexplanation for long-term survival in this model.While not a complete explanation, this finding regard-ing urokinase is interesting and it may be a contributingfactor in survivorship in these Li-treated mice and assistin protection against loss of tubule integrity. Urokinaseis produced by convoluted proximal tubule cells and thethick ascending limb of Henle’s loop [46]. Tubule epithe-lial cells also express receptors for urokinase, a findingthat may also be relevant for the localization of the uro-kinase (discussed in [45]). Therefore, there is associatedevidence that urokinase could be involved in long-termrenal protection, but this proteinase cannot explain thefact that only a subset of Li-treated mice are long-termsurvivors as all mice on Li treatment exhibited elevatedurokinase mRNA levels.As mentioned above, all Li-treated female NZB/Wmice developed polydipsia, and so these associatedchanges also do not explain the ~50 % long-term survi-vors when treated with 4 mg LiCl per day [25]. Interest-ingly, Rojek et al. [47] have shown in rat models that anumber of renal genes are expressed differently follow-ing lithium treatment and induction of polydipsia.Therefore, this approach should likely be repeated withNZB/W female mice +/− Li treatment to gain further in-sights in this model. Other investigators have also ad-vanced the concept that Li is an excellent tool to studyrenal physiology and biochemistry (reviewed in [48]).Interestingly, studies using isolated porcine proximal tu-bule cells in vitro have indicated they are very resistant todamage by Li [49]. In contrast, Li treatment of porcinedistal tubule cells in vitro lead to apoptosis of this porcinecell line (PK (15)) [50]. Thus, different cell populations inthe kidney may be responding to Li exposure in a hetero-geneous manner. Whether this resistance of porcine prox-imal tubule cells can be extended to the analogous murinecells is not known. Unfortunately, in the autoantibodystudies described above (42), we used porcine cell line (PK(15) and LLC-Pk1) cell lysates but did not use Li-treatedporcine tubule cells for comparison to assess whether Litreatment led to alterations in detection of specific proteintargets. Such further studies in pig models may lead tovaluable information in this regard.However, these findings in Li-treated NZB/W micecould be revisited using improved molecular technologiesto better quantify the molecular and cellular changes oc-curring and to investigate the potential underlying mecha-nisms leading to a long-term survivorship while on Li inmore detail. Perhaps, focusing on lithium-mediated effectson G-protein signaling [51], or molecules such as e-selectin [52] which contribute to macrophage adhesionand subsequently, participates in lupus nephritis [53].Relevant to this discussion is the fact that regulation of e-selectin expression involves the GSK-3 pathway, a path-way that can be regulated by LiCl [54, 55].Possible molecular mechanisms underpinning Li action inNZB/W female micePotential direct effects of Li on the kidneyAs mentioned above, Li treatment led to induction ofpolydipsia in all mice, and as this is likely due to an ef-fect on collecting tubule ducts, this is evidence of a dir-ect impact of Li on these cells. Other in vitro studiesexamining the effect of Li salts on porcine renal tubulecells revealed that Li induced apoptosis in the PK(15)tubular cell line [50], but the porcine proximal tubulecell line LLC-PK-2 was very tolerant to similar concen-trations of Li [49]. While these two cell lines have beenadapted to growth under in vitro conditions, the findingsdo potentially indicate that tubule cells derived from dif-ferent parts of the kidney may respond to Li differently.At the molecular level, as discussed above, Li can in-fluence a number of intracellular pathways, and pres-ently, it is not clear which one(s) are affected by in vivotreatment of the NZB/W mice. Of particular interest isthe glycogen synthase kinase-3 (GSK-3) pathway whichhas become important in a number of systems (reviewedin [54, 55]) and the Wnt and beta-catenin pathways dis-cussed earlier. LiCl is known to inhibit renal GSK-3 ac-tivity in C57Bl/6 mice [55]. Perhaps, with the availabilityof a large number of inhibitors for several potential Litargets becoming commercially available, this could berevisited to gain more detailed understanding of poten-tial direct influences of Li on renal cells.Potential indirect effects of LiInterestingly, as a consequence of the LiCl treatment offemale NZB/W mice, they failed to gain weight and, spe-cifically, failed to deposit the usual subcutaneous andintra-abdominal fat [25, 26]. The lack of fat depositionwas complete and the mice closely maintained theirstarting weights. Once treatment was stopped, the sur-viving mice again started to deposit fat. The basis forthis fat deposition is unknown and its relationship to theSLE symptoms and disease progression also unknown.At the time the studies were performed, the observationwas interesting, but how it could be associated with theHart Biology of Sex Differences  (2016) 7:31 Page 5 of 10renal function and immune parameters was not overtlyevident. However, it is reported that obesity is associatedwith the development of a number of autoimmune dis-eases [56], so there may also be linkages between pro-gression of disease via secondary sequelae (e.g., renalinvolvement) and obesity.However, it has been reported that caloric restrictionof female NZB/W mice leads to a decline in cytokine ex-pression and disease progression irrespective of dietaryfat [57]. More recently, a focus on obesity has revealedthat obesity is associated with development of a meta-bolic disease, accompanied by a systemic inflammation(discussed in [58, 59]), as well as the other impacts ofobesity on the kidney [60]. Furthermore, such metabolicdisease may be a risk factor for renal disease (discussedin [58, 59]). Therefore, it may be necessary to return tothe mechanisms of fat deposition in this model and theconsequences of it as the SLE-like disease progresses, asit may also be a contributing factor in the diseaseprocess and the renal response to Li. However, Li treat-ment affected fat deposition in 100 % of the NZB/Wwhen treatment was started at 8–10 weeks of age, a timewhen only ~50 % of the mice were destined to be long-term survivors. Thus, the fat deposition aspect of the Litreatment may be only a contributing factor, and sec-ondary to some as yet, undefined specific target re-sponse. However, while an impact on diet-related factorsmay not account for all of the Li effects on NZB/NZWfemale mice, it could be a regulatory component of theimpact which allows or permits some other Li-specifictarget(s) to exert a strong impact on survival.Thus, Li effects on disease progression in NZB/NZWfemale mice may relate, in part, to what the animals arefed or their nutritional status. Mice housed in a univer-sity vivarium are usually fed a standard chow diet that iscommercially available (most are casein- or corn-baseddiets), a diet likely not very similar to what a mousewould subsist on in the wild. This scenario sets the stageto ask whether Li treatment was affecting, in as yet un-identified manners, the impact of this artificial diet onthe immune system, the kidney, an obesity-induced al-tered inflammatory state, and/or even the mouse micro-biome [61] of these susceptible NZB/NZW mice.Relevant to this discussion is a report by Chandrasekarand Fernandes [62] which indicated that NZB/NZW fe-male mice fed a diet rich in omega-3 lipids exhibited de-creased pro-inflammatory cytokine expression, as well asincreased antioxidant gene expression. The treated micehad an extended life-span, similar to the mice treatedwith a single dose of Li/day starting at the age of 8 weeks.However, in the Chandrasekar and Fernandes studies,the mice on the omega-3 rich diet weighed the same asthe untreated mice [62]. Therefore, Li treatment couldbe impacting the negative influence of the chow diet ondisease development and progression, in part like theomega-3 rich diet, but with some additional metabolictargets, possibly mediated by glycogen synthase kinase-3beta (GSK-3beta; [54, 55]). Interestingly, a number of re-ports in a variety of murine lupus models [63–67], in-cluding the MRL-lpr model and the NZB/NZW modelwith females, have supported the concept of dietary in-fluences on disease development and progression, in-cluding nephritis. Therefore, Li effects on long-termsurvival may involve multiple targets due to its range ofmetabolic influences.Of note, it has been reported that obesity is commonin patients with SLE (discussed in [56]). If this possibilityproves to have validity from future investigations, then itmay require stepping back and re-evaluating potentialinductive and exacerbating signals for SLE developmentand progression.Could genetics play a role in the observed protection offemale NZB/W mice with lithium?In humans, it is clear that the genetics are complex andlikely include contributions from kidney-related genes[15]. It is also clear that NZB/W mice are an F1 betweenthe two parental strains (NZB and NZW) and that bothparental strains contribute genes to the F1 SLE pheno-type (reviewed in [19, 20] and others). Thus, the findingthat ~50 % of the female NZB/W mice were long-termsurvivors after initiation of treatment with 4 mg LiCl perday at 8–10 weeks of age raised the potential interpret-ation that one half of the mice expressed some geneticsusceptibility from one parent vs the other. However, in-creasing the dose of LiCl to 2 × 4 mg/day leads to long-term survival of ~80 % of the mice [41], and therefore,the higher dose appeared to overcome some limitationsof the 4 mg dose, findings which would tend to temperthe interpretation that long-term survival was associatedwith the genetics of one parent vs the other.To begin to better understand some of the potentialstrain-specific effects of LiCl treatment, the response ofa number of commercially available mouse strains (eightstrains from Jackson Laboratories), including the paren-tal strains (NZB and NZW), to LiCl treatment wasundertaken. The induction of polydipsia in some strainswas induced by lower LiCl concentrations than others[68, 69], and in some strains, polydipsia was not overtlyinduced even by 4 mg LiCl/day. Of particular interestwas the finding that induction of polydipsia in NZB andC57BL/6 mice occurred at low doses, while higher doseswere required for NZW and BALB/c, and the modestdoses were apparently toxic for A/J mice. The responseof DBA and C3H/HeJ mice was intermediate to that ofthe NZB and C57BL/6 mice. What is very interestingfrom these data is the fact that the NZB and C57BL/6mice are black and all of the low/negative respondersHart Biology of Sex Differences  (2016) 7:31 Page 6 of 10had a white coat color. Furthermore, albino C57BL/6mice were still responsive to Li induction of polydipsia,so that the coat color contributions were likely not dir-ectly involved in polydipsia induction (Hart, unpublishedobservations). Interestingly, tyrosine hydroxylase hasalso been reported to not be associated with lithiumresponsiveness in patients with affective disorders [70].Furthermore, African-Americans and Hispanics moreresponsive to low-dose lithium than are Whites [71].Therefore, the response patterns to LiCl in mousestrains may provide some insights to effectiveness inhumans, but it is not yet clear whether there will also besex differences in this regard.Other investigations using very different readouts (e.g.,brain functioning) have also found somewhat similar re-sults regarding coat color [72]. In those studies, C57BL/6 and Black Swiss mice were Li-responders, but CD-1and NIH Swiss mice (e.g., white coats) were non-responders to Li treatment. Again, C3H/HeJ mice weremodestly influenced by the Li treatment. Therefore, therelationship between coat color and lithium effectivenessis likely a more general phenomenon but could have im-pacted the responsiveness of the BXSB and MRL-lprmice in addition to sex!The common finding of black coat color being rele-vant to Li responsiveness is very interesting and may in-dicate that in the studies detailed with NZB/W F1 mice,and in spite of the above discussion regarding long-termsurvivorship, Li may be primarily influencing genes pro-vided by the NZB parent, but this speculation remainsto be confirmed.Interestingly, treatment of female NZB/W F1 micewith alpha-melanocyte stimulating hormone did notprovide any significant renal protection, so that hormoneis likely not involved in long-term survivorship while onLi [73]. In contrast, alpha-MSH is reported to ameliorateSLE-like activity in the pristine-induced mouse model[74]. Furthermore, alpha-MSH has been reported tohave potent anti-inflammatory activities and protectagainst acute renal failure in rodent models, possibly bydirect effects on renal tubules via melanocortin recep-tors [75]. Therefore, the inability of alpha-MSH to pro-tect against renal failure in the female NZB/NZW modelis at odds with some of the literature regarding alpha-MSH and acute renal insults and may be due to thechronic nature of the SLE-mediated effects or perhapsdue to other non-melanocortin receptor associatedevents.As the genetic basis for mouse coat color and humanpigmentation is very complex [76–81], the relationshipsto renal functioning after Li treatment may be very com-plicated as well, particularly given the sexual dimorph-ism observed for Li treatment in the NZB/W mice.However, there may be some “common ground” forsome of the observations related to Li affects on the fe-males. That is, the melanocortin system may be involvedin coat color, as well as obesity (reviewed in [77, 81])and the renal system (discussed in [80]). Interestingly,mutations in the melanocortin-4 receptor are associatedwith early onset obesity in humans and in mice [81].Therefore, it is possible that Li may be affecting ele-ments of a single, as yet undefined, system to modify thekidneys of these mice, as well as the loss of fat that wasobserved.Additional considerations regarding why LiCl treatment iseffective in female NZB/W miceIn the NZB/W model, as discussed above, it is knownthat subjecting females to ovariectomy leads to an inhib-ition of disease development and progression (reviewedin [19, 20]), while castration of males leads to an en-hancement of the disease progression (reviewed in [19,20]). However, whether this is due to immune variablesor renal variables cannot be ascertained in detail. Inter-estingly, the association of Li effectiveness with the onsetof puberty, and the lack of effect in males, may indicatethat the targets of Li treatment are related to either sexhormone modifications to the kidney or as yet un-detected immune dysfunction, and the current findingsare consistent with the above information. Interestingly,the presence of two X chromosomes vs a XY comple-ment has been reported to impact the onset and pro-gression of disease on a pristine-induced lupus model[82]. Furthermore, whether the cells in target tissues ex-press estrogen receptor alpha or beta (ER-alpha or ER-beta) may also play a role in gene expression (discussedin [83–85]) via hormone response elements (complexesof ER + hormone) or via formation of complexes withother transcription factors (discussed in [83–85]). Thus,ER can regulate gene expression alone, as well as incomplexes with hormone. Interestingly, estrogen recep-tors in NZB/W mice are reported to be variants com-pared to those in non-SLE mouse strains (reviewed in[86]). Thus, regulation of gene expression by such vari-ants may predispose for SLE development and progres-sion. Therefore, the “how” of Li effects is still not clearassuming there is a direct link between the kidney andLi, in addition to other potential targets.Much of the above discussion has focused on the“how” LiCl treatment could be influencing female NZB/W mice, but the real question relates to the “why” be-hind the observations! The why may also relate to pre-paring the kidney for pregnancy-related events (e.g.,mineral retention for a successful pregnancy, specificcell-type alterations to retain nutrients during pregnancyto transfer to the offspring, or an increased demand ongeneral renal function due to carrying large litters (e.g.,control of hypertension), or other female-specificHart Biology of Sex Differences  (2016) 7:31 Page 7 of 10activities related to successful pup survival (e.g., lacta-tion)). Such speculations must await further investiga-tion, but such possibilities can be addressed usingmodern molecular, biochemical, and genetic tools.Are the Li treatment of NZB/W female mice findingsrelevant to human SLE?The other important questions of the “why and how” is-sues relate to extrapolation of the mouse findings tohumans. These are critical questions as considerablegrant funding has gone into understanding these mousemodels, with the hope that the findings are relevant tothe human condition. In humans with SLE, ~90 % of pa-tients are female, but the incidence of nephritis is higherin the population of males than in the females [87–90],but ethnic variables (black, white, Asian) appear to alsoplay relevant roles in the sexual dimorphism [91–93].Interestingly, males are often older when the disease isdiagnosed, and some of these men have low sex hor-mone levels.Thus, by numbers alone, there are more females withlupus nephritis than males, but even in the small per-centage of males, it is common and can be more severe[9, 86–93]. Therefore, development and progression oflupus nephritis is either mechanistically different inmales and females, or the findings in NZB/W mice can-not be readily extrapolated to humans and thus are re-stricted to mice with a specific background/geneticmakeup (e.g., they are mice after all with millions ofyears of optimizing their regulatory systems for survivalof the species). There are however some areas of con-cordance between murine coat pigmentation with hu-man skin color, as in human patients with SLE, thereappears to be more renal involvement in non-Caucasians than Caucasians (discussed in [9, 88, 93]).Thus, in Caucasians, there may have been some loss offunction associated with skin color during evolution thatdid not compromise survival of that subset of humans.Therefore, whether the “why” of the findings with LiCland NZB/W mice can potentially be translated tohumans remains to be determined, but using compara-tive systems biology approaches, additional commonal-ities may be elucidated.SummaryLi treatment has been shown to influence disease coursein murine models of SLE for females, but not males. Inparticular, the response of female NZB/W mice to Li isdramatic from the perspective of survivorship and main-tenance of renal function. Li treatment has been shownto alter a number of parameters at the level of the kid-ney (e.g., prevention of renal sclerosis, induction of uro-kinase, and induction of polydipsia), but these have notbeen directly linked to long-term survivorship while onLi. Indirect effects of Li (e.g., inhibition of fat deposition)were also shown but again were not directly linked tolong-term survivorship. While no overt influences of Litreatment on autoimmunity were detected, the spectrumassessed in this regard was limited. Therefore, a numberof direct and indirect influences of Li treatment on fe-male NZB/W mice were detected, but it is not yetknown if and how such changes are related to long-termsurvivorship. Long-term survivorship could be dependenton the constellation of changes observed rather than a sin-gle alteration, or the constellation of changes could facili-tate the effectiveness of as yet known effects of the Li toaccount for the percentage of female NZB/W mice exhi-biting long-term survivorship while on Li.ConclusionsThe above discussion has provided evidence that Litreatment of murine models of SLE yields varied out-comes. However, the impact on females of the NZB/WF1 strain is profound, and treatment protects a largepercentage of the treated animals from end-stage renalfailure without detectable impact on immune aberra-tions. While it is possible that Li treatment did exertsome influences on autoimmunity in the female NZB/Wmice, it is clear that Li treatment modified the impact ofautoimmune dysfunction on the kidney, leading to alow-grade glomerulonephritis without conversion totubulosclerosis and renal failure. This in itself is remark-able and offers researchers opportunity to pursue the in-vestigations to elucidate the mechanisms underlyingsuch target organ resistance. The underlying basis occur-ring in females and not males is also somewhat remark-able given the fact that in patients, 90 % are female. Atthe genetic level, it is also clear that one likely has toseparate immune dysfunction (e.g., autoimmunity) fromend-organ susceptibility, and the studies presented hereoffer a route to explore such differences in detail.While there are some parallels between the murinemodels and patients with SLE (e.g., influence of sex, eth-nicity, renal involvement, etc.), it is unlikely that Li treat-ment of patients with SLE will or should occur, andother aspects of human SLE are different from the mur-ine models. Firstly, humans likely will not tolerate thecomparable levels of Li required to elicit a response inthe NZB/W mice. The use of Li salts to treat affectivedisorders in patients, such as bipolar disease, uses con-centrations of Li that are close to toxic, and side effectsare common. Secondly, patients on Li usually gainweight rather than lose it (reviewed in [94]), possibly in-dicating that the molecular targets in humans may besomewhat different. Therefore, more detailed study ofthe effect of Li on protecting end-organ integrity in theNZB/W model may provide important clues as to themolecular basis for the protection, but the tool toHart Biology of Sex Differences  (2016) 7:31 Page 8 of 10achieve the goal (e.g., Li) may not be directly translatedto patient populations. However, elaboration of themechanisms involved in the NZB/W model may provideuseful information regarding the complexity of the prob-lem in human populations.AcknowledgementsThe author thanks the many trainees who worked on several of the projectsdescribed in this review and the international and local colleagues who haveparticipated in discussions over the past few decades regarding the resultspresented. The support of the Calgary Foundation-Grace Glaum Professorshipis gratefully acknowledged.Competing interestsThe author declares that he has no competing interests.Author details1Department of Surgery, Wound Healing Initiative, McCaig Institute for Boneand Joint Health, University of Calgary, 3330 Hospital Drive NW, Calgary,Alberta T2N 4N1, Canada. 2Faculty of Kinesiology, University of Calgary,Calgary, Alberta, Canada. 3Centre for Hip Health and Mobility, University ofBritish Columbia, Vancouver, British Columbia, Canada.Received: 12 April 2016 Accepted: 22 June 2016References1. 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