Effect of mycophenolate and rapamycin on renal fibrosis in lupus nephritis

Abstract

Lupus nephritis (LN) leads to chronic kidney disease (CKD) through progressive fibrosis. Mycophenolate inhibits inosine monophosphate dehydrogenase and is a standard treatment for LN. The mammalian or mechanistic target of rapamycin (mTOR) pathway is activated in LN. Rapamycin inhibits mTOR and is effective in preventing kidney transplant rejection, with the additional merits of reduced incidence of malignancies and viral infections. The effect of mycophenolate or rapamycin on kidney fibrosis in LN has not been investigated. We investigated the effects of mycophenolate and rapamycin in New Zealand Black and White first generation (NZB/W F1) murine LN and human mesangial cells (HMCs), focusing on mechanisms leading to kidney fibrosis. Treatment of mice with mycophenolate or rapamycin improved nephritis manifestations, decreased anti-double stranded (ds) DNA antibody titer and reduced immunoglobulin G (IgG) deposition in the kidney. Both mycophenolate and rapamycin, especially the latter, decreased glomerular mTOR Ser2448 phosphorylation. Renal histology in untreated mice showed mesangial proliferation and progressive glomerulosclerosis with tubular atrophy, and increased expression of transforming growth factor β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen. Both mycophenolate and rapamycin ameliorated the histopathological changes. Results from in vitro experiments showed that both mycophenolate and rapamycin decreased mesangial cell proliferation and their binding with anti-dsDNA antibodies. Mycophenolate and rapamycin also down-regulated mTOR and extracellular signal-regulated kinase (ERK) phosphorylation and inhibited fibrotic responses in mesangial cells that were induced by anti-dsDNA antibodies or TGF-β1. Our findings suggest that, in addition to immunosuppression, mycophenolate and rapamycin may reduce fibrosis in LN, which has important implications in preventing CKD in patients with LN.

Integrated analysis of the molecular mechanisms in idiopathic pulmonary fibrosis

“…Among the functions and pathways we have obtained, some functions or pathways have been proved to be involved in the regulation of pulmonary fibrosis, and some have not been reported. Inosine monophosphate (IMP) and uridine triphosphate (UTP) have not been found in IPF, but IMP is involved in the fibrotic process of lupus nephritis (LN) 41 . Whether the metabolic processes of IMP and UTP are involved in the process of pulmonary fibrosis awaits further investigation.…”

Comprehensive Analysis of Urinary lncRNA And mRNA Expression Profiles In Patients With lupus Nephritis

“…Oxidative phosphorylation (OXPHOS) produces more than 95% of a cell's energy in the form of ATP mainly from mitochondrial one.Research found the association of common variants of the adenosine triphosphate 6q(ATP6) genes with SLE,which raises the possibility of a shared mitochondrial genetic background of LN [39].The mTOR mentioned above forms two distinct multiprotein complexes, mTORC1and mTORC2.mTOR is a serine/threonine kinase and expresses a phosphoinositide 3-kinase (PI3K)-related kinase family.The mTOR signaling pathway is closely associated with immune cells,the abnormalities of autophagy and OS,and plays an important role in the pathogenesis of LN.A clinical study found that rapamycin/sirolimus(mTOR Inhibitor),a drug currently approved to prevent organ transplant rejection,may offer a safe and effective treatment for lupus by blocking T cell function and decreasing mitochondrial dysfunction by activating mitophagy [40].The process is regulated by the autophagy-related gene family, While the atg5 gene has been linked to the development of LN by epigenetic studies. mTOR pathway guides the development of novel and effective therapies for patients with LN [41].The mitophagy pathway is an important form of autophagy for the selective removal of dysfunctional or redundant mitochondria.Pro cient mitophagy may have therapeutic effects in LN,and drugs that induce mitophagy,such as rapamycin works in exploration as therapeutic strategies to enhance the clearance of injury-promoting fragmented mitochondria and accelerate recovery from LN ares [42,43].…”

A review of advances in the understanding of lupus nephritis pathogenesis as a basis for emerging therapies

“…The mammalian or mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine-threonine kinase that plays a key role in the regulation of cell proliferation, metabolism, and survival. Increased mTOR activation is observed in patients and mice with LN 95 . Sirolimus is a naturally occurring macrolide antibiotic produced by Streptomyces hygroscopicus and is a specific inhibitor of the mTOR pathway.…”

“…There is also emerging evidence that the anti-proliferative property of mTOR inhibitors extends beyond lymphocytes to non-immune cells. We recently demonstrated that sirolimus decreased mesangial cell proliferation and their binding by anti-dsDNA antibodies and suppressed fibrotic responses in mesangial cells when cells were exposed to anti-dsDNA antibodies or transforming growth factor (TGF)-β1, and the effect was mediated through down-regulation of mTOR and extracellular signal-regulated kinase phosphorylation 95 . In NZB/W F1 mice with active nephritis, sirolimus was as effective as mycophenolate in attenuating kidney inflammation and fibrosis 95 .…”

“…We recently demonstrated that sirolimus decreased mesangial cell proliferation and their binding by anti-dsDNA antibodies and suppressed fibrotic responses in mesangial cells when cells were exposed to anti-dsDNA antibodies or transforming growth factor (TGF)-β1, and the effect was mediated through down-regulation of mTOR and extracellular signal-regulated kinase phosphorylation 95 . In NZB/W F1 mice with active nephritis, sirolimus was as effective as mycophenolate in attenuating kidney inflammation and fibrosis 95 . A recent single-arm phase I/II study (NCT00779194) reported that sirolimus treatment in patients with active SLE but without nephritis or life-threatening lupus complications resulted in a decrease in disease activity score and a T cell profile indicating a less pro-inflammatory phenotype 100 .…”