Antiproteinuric Effect of Chemokine C-C Motif Ligand 2 Inhibition in Subjects with Acute Proliferative Lupus Nephritis

Blé, Alessandro; Mosca, Marta; Loreto, Giorgio Di; Guglielmotti, Angelo; Biondi, Giuseppe; Bombardieri, Stefano; Remuzzi, Giuseppe; Ruggenenti, Piero

doi:10.1159/000330685

Cited by 48 publications

(37 citation statements)

References 29 publications

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“…In adjuvantinduced arthritis in rats, bindarit treatment led to a drastic reduction of radiological scores assigned based on joint effusion and bone erosion, reflective of a protective effect (43,74,75). The safety of bindarit has been demonstrated in an SLE clinical trial: bindarit treatment was safe and well-tolerated in patients, and there was no evidence of immunosuppressive effects on acquired immunity (76). Although bindarit has also been associated with inhibition of other immune mediators, including TNF (43) and IL-12 (48), CCL2 remains the best-characterized target of bindarit.…”

Section: Discussionmentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

109

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The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

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Section: Discussionmentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

109

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“…In murine lupus nephritis, bindarit reduced MCP-1 mRNA overexpression and signs of inflammation in the kidney, delayed the development of proteinuria and renal damage, and prolonged survival [19]. Moreover, in patients with acute proliferative lupus nephritis, bindarit significantly reduced albuminuria and urinary MCP-1 levels [20]. …”

Section: Discussionmentioning

confidence: 99%

Effects of MCP-1 Inhibition by Bindarit Therapy in a Rat Model of Polycystic Kidney Disease

Zoja

Corna

Locatelli

et al. 2014

Nephron

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Background/Aims: Experimental and clinical evidence suggested that monocyte chemoattractant protein-1 (MCP-1/CCL2) has a role in the development of interstitial inflammation and renal failure in polycystic kidney disease (PKD). We investigated whether bindarit, an inhibitor of MCP-1/CCL2 synthesis, could influence the evolution of PKD in PCK rats. Methods: PCK rats were treated from 5 to 15 weeks of age with vehicle or bindarit. Sprague-Dawley rats served as control. For in vitro studies, murine podocytes were exposed to albumin with or without bindarit. Results: MCP-1 mRNA was upregulated in the kidney of PCK rats and reduced by bindarit. Treatment limited overexpression of MCP-1 protein by epithelial cells of dilated tubules and cysts, and interstitial inflammatory cells. Excessive renal accumulation of monocytes/macrophages was lowered by bindarit by 41%. Serum creatinine slightly increased in PCK rats on vehicle and was similar to controls after bindarit. Kidney and liver cysts were not affected by treatment. Bindarit significantly reduced progressive proteinuria of PCK rats. The antiproteinuric effect was associated with the restoration of the defective nephrin expression in podocytes of PCK rats. Bindarit limited podocyte foot process effacement and ameliorated slit diaphragm frequency. In cultured podocytes, bindarit reduced MCP-1 production in response to albumin and inhibited albumin-induced cytoskeletal remodeling and cell migration. Conclusion: This study showed that although bindarit did not prevent renal cyst growth, it limited interstitial inflammation and renal dysfunction and reduced proteinuria in PKD. Thus, bindarit could be considered a therapeutic intervention complementary to therapies specifically acting to block renal cyst growth.

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“…111 It reduced albuminuria in two small studies in macroalbuminuric patients with lupus nephritis 112 or type 2 diabetes, 113 but adequately powered trials are needed to assess whether this beneficial effect may actually translate into slower progression in the long term.…”

Section: What Is New In the Pipeline?mentioning

confidence: 99%

Mechanisms and Treatment of CKD

Ruggenenti

Cravedi

Remuzzi

2012

Journal of the American Society of Nephrology

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242

183

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As CKD continues to increase worldwide, along with the demand for related lifesaving therapies, the financial burden of CKD will place an increasing drain on health care systems. Experimental studies showed that glomerular capillary hypertension and impaired sieving function with consequent protein overload play a pathogenic role in the progression of CKD. Consistently, human studies show that proteinuria is an independent predictor of progression and that its reduction is renoprotective. At comparable BP control, inhibitors of the renin-angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), more effectively than non-RAS inhibitor therapy reduce proteinuria, slow progression to ESRD, and even improve the kidney function achieving disease regression in some cases. In participants with diabetes, RAS inhibitors delay the onset of microalbuminuria and its progression to macroalbuminuria, and ACE inhibitors may reduce the excess cardiovascular mortality associated with diabetic renal disease. In addition to RAS inhibitors, however, multimodal approaches including lifestyle modifications and multidrug therapy will be required in most cases to optimize control of the several risk factors for CKD and related cardiovascular morbidity. Whether novel medications may help further improve the cost-effectiveness of renoprotective interventions is a matter of investigation.

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Antiproteinuric Effect of Chemokine C-C Motif Ligand 2 Inhibition in Subjects with Acute Proliferative Lupus Nephritis

Cited by 48 publications

References 29 publications

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Effects of MCP-1 Inhibition by Bindarit Therapy in a Rat Model of Polycystic Kidney Disease

Mechanisms and Treatment of CKD

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