Sex-specific effects of LiCl treatment on preservation of renal function and extended life-span in murine models of SLE: perspective on insights into the potential basis for survivorship in NZB/W female mice

Abstract

Considerable research effort has been invested in attempting to understand immune dysregulation leading to autoimmunity and target organ damage. In systemic lupus erythematosus (SLE), patients can develop a systemic disease with a number of organs involved. One of the major target organs is the kidney, but patients vary in the progression of the end-organ targeting of this organ. Some patients develop glomerulonephritis only, while others develop rapidly progressive end organ failure. In murine models of SLE, renal involvement can also occur. Studies performed over the past several years have indicated that treatment with LiCl of females, but not males of the NZB/W model, at an early age during the onset of disease, can prevent development of end-stage renal disease in a significant percentage of the animals. While on Li treatment, up to 80 % of the females can exhibit long-term survival with evidence of mild glomerulonephritis which does not progress to renal failure in spite of on-going autoimmunity. Stopping the treatment led to a reactivation of the disease and renal failure. Li treatment of other murine models of SLE was less effective and decreased survivorship in male BxSB mice, exhibited little effect on male MRL-lpr mice, and only modestly improved survivorship in female MRL-lpr mice. This perspective piece discusses the findings of several related studies which support the concept that protecting target organs such as the kidney, even in the face of continued immune insults and some inflammation, can lead to prolonged survival with retention of organ function. Some possible mechanisms for the effectiveness of Li treatment in this context are also discussed. However, the detailed mechanistic basis for the sex-specific effects of LiCl treatment particularly in the NZB/W model remains to be elucidated. Elucidating such details may provide important clues for development of effective treatment for patients with SLE, ~90 % of which are females.

Human Heterogeneity and Survival of the Species: How Did It Arise and Being Sustained?—The Conundrum Facing Researchers

“…This loss may have accompanied migration to latitudes that required better vitamin D metabolism, and thus, loss of pigmentation that could interfere with such metabolism (discussed in [26]). However, this may have had consequences for other areas such as regulation of inflammation [27] and it is known that humans of the Black race and black mice both respond to lower doses and differently to the metabolic modulator lithium chloride/carbonate (discussed in [28]). In addition, the loss of pigmentation could relate to the melanocortins and their receptors, and lead to development of more skin cancer risk if the affected individuals migrated back to their central African origins [29].…”

Would Adding Low Doses of Lithium Salts and/or Prebiotic Fibre Interventions to an Effective Exercise Protocol Further Enhance Retention of Cognitive Integrity? Potential for Preventing Loss of Cognition with Aging Using Combinations of Low Cost Regimens

“…As Mg and Na are common co-factors in enzymes, Li can thus impact a variety of important biologic systems including NaK ATPases, cyclic AMP metabolism, GSK-3beta function, and others [41][42][43][44]. Interestingly, in both humans and mice, somewhat lower doses of Li salts are effective in those of Black races and in mice with black coat color [41,46]. Furthermore, in rodent models, Li salts were only effective in females and not males with regard to autoimmune diseases and obesity risk [46].…”

“…Interestingly, in both humans and mice, somewhat lower doses of Li salts are effective in those of Black races and in mice with black coat color [41,46]. Furthermore, in rodent models, Li salts were only effective in females and not males with regard to autoimmune diseases and obesity risk [46]. Relevant to the above discussion on exercise and the vascular system, Li can also impact endothelial cells [47].…”

“…However, for those more interested in mechanisms of action, purified 7 Li and 6 Li preparations could be used to elaborate more detail in this regard. In fact, the author has used such purified preparations in the past for rodent studies [46]. If Li supplementation alone leads to the identification of "responders and non-responders", then the findings could lead to new precision medicine tools to better understand disease processes in subset of patients/potential patients.…”

“…In rodents, administration of lithium salts both prevented autoimmune disease progression in a murine model (but only in females), as well as weight gain and fat deposition [46]. However, human patients taking high doses of lithium salts for bipolar disease often gain weight [46].…”