Cyclic GMP catabolism up-regulation in MRL/lpr lupus-prone mice is associated with organ remodeling

Abstract

Production of high titer of antibodies against nuclear components is a hallmark of systemic lupus erythematosus, an autoimmune disease characterized by the progressive chronic inflammation of multiple joints and organs. Organ damage and dysfunction such as renal failure are typical clinical features in lupus. Cell hypermetabolism and hypertrophy can accelerate organ dysfunction. In this study we focus on a specific murine model of lupus, the MRL/lpr strain, and investigated the role of cyclic guanosine monophosphate (cGMP) catabolism in organ remodeling of main target tissues (kidney, spleen and liver) in comparison with age-matched control mice. In MRL/lpr-prone mice, the cGMP-phosphodiesterase (PDE) activities were significantly increased in the kidney (3-fold, P<0.001), spleen (2-fold, P<0.001) and liver (1.6-fold, P<0.05). These raised activity levels were paralleled by both an increased activity of PDE1 in the kidney (associated with nephromegaly) and in the liver, and PDE2 in the spleen of lupus-prone mice. The up-regulation of PDE1 and PDE2 activities were associated with a decrease in intracellular cGMP levels. This underlines an alteration of cGMP-PDE signaling in the kidney, spleen and liver targeting different PDEs according to organs. In good agreement with these findings, a single intravenous administration to MRL/lpr mice of nimodipine (PDE1 inhibitor) but not of EHNA (PDE2 inhibitor) was able to significantly lower peripheral hypercellularity (P=0.0401), a characteristic feature of this strain of lupus-prone mice. Collectively, our findings are important for generating personalized strategies to prevent certain forms of the lupus disease as well as for understanding the role of PDEs and cGMP in the pathophysiology of lupus.

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

“…2). It is worth mentioning that a single intravenous administration to MRL-lpr mice of nimodipine (PDE1 inhibitor) but not of EHNA (PDE2 inhibitor) was able to significantly lower peripheral hypercellularity [175], which is a typical feature of this strain of lupus mice (see above). It remains to be explored if drugs known to inhibit cAMP-PDE3 activity are able to display such an effect and possibly reverse some neurological signs observed in this mouse model.…”

“…PDE1 activity levels were raised in their kidneys (associated with nephromegaly) and liver, and PDE2 activity was specially increased in their spleen [175]. Nearly all the PDE families are expressed in the CNS [176].…”

“…Basal cAMP-PDE specific activities in total homogenate (A) and contribution of PDE3 (B) and PDE4 (C) were assessed on 15 week-old CBA/J and MRL-lpr mice as described by Yougaré and collaborators[175]. Data are expressed as pmol/min/mg of protein and are the mean ± s.e.m.…”

Cyclic Nucleotide Signalling in Kidney Fibrosis

“…In MRL/lpr lupus-prone mice PDE1 activity was elevated in the kidney, which was accompanied by a decrease in cGMP levels. Treatment with nimodipine resulted in improvement of organ remodeling, especially kidney remodeling, as well as in reduction of hypercellularity [ 131 ].…”

Interleukin-6: A Proinflammatory Role in Nephritis in Patients with Systemic Lupus Erythematosus

“…In spite of extensive research, there are still unanswered questions regarding the role of inflammation in the pathogenesis of renal damage in systemic lupus erythematosus [11][12][13] and furthermore the implication of IL-6 in the initiation of inflammatory cascade. The aim of current study was to detect the serum level of IL-6 in SLE patients.…”