The renin-angiotensin system in lupus: physiology, genes and practice, in animals and humans

Abstract

Although multiple studies suggest a potential role for angiotensin II in inflammation, most were performed either in vitro or in animals with non-immune-complex-mediated diseases. Extrapolation of these findings to humans, particularly patients with lupus, which involves multiple immunoregulatory pathways, is unclear. In autoimmune-prone MRL/lpr mice, angiotensin-converting-enzyme (ACE) inhibition improved survival although to a lesser degree than cyclophosphamide and diminished the glomerular histopathologic damage, proteinuria, lymphoid hyperplasia, dermatitis, and hypergammaglobulinemia, with a reduction in TGF-beta1 and beta 2 expression in the kidneys and renal chemokine mRNA expression. Spleen levels of IL-4 and IL-10 were also reduced. Uncontrolled studies in patients with treatment-refractory lupus nephritis showed a significant reduction in proteinuria with ACE-inhibitors and Angiotensin receptor blockers treatment. The 'masking' effect of ACE-inhibitors should be taken into consideration, as an exacerbation of lupus nephritis may be missed when estimated by the magnitude of proteinuria, which is decreased by these treatments. No single ACE genotype was consistently associated with subsets of SLE patients. In retrospective analyses, ACE-inhibitor use predicted a favourable outcome in 94 cases of pauci-immune vasculitis. The attenuating effect of angiotensin II inhibitors on the progression of chronic renal disease is well recognized. The data on the role of this intervention in lupus is limited.

Recent advances in the treatment of lupus nephritis

“…An animal study has highlighted the inflammatory components of the RAAS and the potential benefits of RAAS blockade in eliminating the inflammation in lupus nephritis [13]. Moreover, de Albuquerque et al [14] treated lupus-prone mice with captopril and found that captopril delayed the onset of proteinuria when administered to prenephritic mice and slowed the progression of the disease in mice with early and advanced lupus nephritis, but they did not observe any of these results in a control group treated with verapamil.…”

Updates on the Treatment of Lupus Nephritis

“…A number of animal studies have highlighted the inflammatory components of the RAAS and the potential benefits of RAAS blockade in reducing or eliminating this inflammation in lupus nephritis. 14 De Albuquerque et al 15 treated lupus-prone mice with captopril and found that captopril delays the onset of proteinuria when administered to prenephritic mice and slows progression of disease in mice with early and advanced lupus nephritis. These results were not seen in a control group treated with verapamil.…”

Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus

“…Patients with SLE are often treated with blockers of the renin-angiotensin system (RAS) to control blood pressure and reduce proteinuria; however, there is conflicting evidence as to whether angiotensin-converting enzyme inhibition improves renal histopathology during SLE. Although RAS blockade is generally effective for lowering pressure in patients with SLE and can lower the risk of vascular events (36), additional antihypertensive therapies are often required to achieve adequate blood pressure control (54). In addition, there are rare cases in which RAS blockade can cause or exacerbate SLE (4,42).…”