- Email: [email protected]
Reply from the Author
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Letters to the Editor
Reply from the Author We congratulate Perez ´ de Lema et al [1] for their report describing the beneficial effects of treatment with ACE inhibitor or angiotensin receptor antagonist on the development of nephritis in MRL-lpr/lpr mice. That simultaneous studies by our group in NZB/NZW F1 [2], MRL-lpr/ lpr [2], and NZM.2410 (our unpublished data) models of lupus also found similar beneficial effects of treatment with an ACE inhibitor underscores the role of the reninangiotensin system in the pathogenesis of lupus nephritis. Renal protection in both studies appears to involve pathways that do not influence serum autoantibody levels or renal immune complex deposition [1, 2]. In our study, a selective reduction in chronic lesion scores that represent renal fibrosis, but not in the glomerular activity scores that mostly represent glomerular inflammation in NZB/NZW F1 mice, suggests that the protection against lupus nephritis probably involves mechanisms that cause tissue fibrosis. In that regard, type 2 cytokines that we have recently found to promote glomerulosclerosis [3] are consistently reduced in animals treated with the ACE inhibitor. TGFb1 and TGF-b2 isoforms were also selectively reduced in certain locations in the kidneys of treated mice [2]. Additionally, Perez ´ de Lema et al [1] found that glomerular cellularity and renal expression of chemokines such as CCL4 and CCL2 were reduced in animals treated with angiotensin inhibitors. That these authors did not find a reduction in inflammatory cell infiltrates in renal interstitium of the treated animals [1] suggests that modulation of inflammation is less likely to the primary mechanism responsible for renal protection in this system. In
a previous study, MCP-1/CCL2 induced a concentrationdependent increase in TGF-b by activated fibroblasts [4], suggesting the possibility of indirect regulation of collagen synthesis by MCP-1/CCL2 via TGF-b. Thus, we envision a scenario where type 2 cytokines such as IL-4, chemokines such as MCP-1/CCL2, and growth factors such as TGF-b orchestrate to assemble a network that promotes tissue fibrosis and causes chronic lupus nephritis. Understanding mechanisms involved in the regulation and counter-regulation of this network will have significant implications for the prevention of end-stage renal disease. RAM R. SINGH
Cincinnati, Ohio Correspondence to Ram Raj Singh, M.D., Professor of Medicine, 231 Albert Sabin Way, MSB Room 7464, Cincinnati, OH 45267-0563. E-mail: [email protected]
REFERENCES 1. PEREZ DE LEMA G, DE WIT C, NIETO E, et al: Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice. J Pharmacol Exp Ther 307:275–281, 2003 2. DE ALBUQUERQUE DA, SAXENA V, ADAMS DE, et al: An ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2 isoforms in murine lupus nephritis. Kidney Int 65:846–859, 2004 3. SINGH RR, SAXENA V, ZANG S, et al: Differential contribution of IL4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol 170:4818–4825, 2003 4. GHARAEE-KERMANI M, DENHOLM EM, PHAN SH: Costimulation of fibroblast collagen and transforming growth factor beta 1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 271:17779–17784, 1996
Letters to the Editor
Reply from the Author We congratulate Perez ´ de Lema et al [1] for their report describing the beneficial effects of treatment with ACE inhibitor or angiotensin receptor antagonist on the development of nephritis in MRL-lpr/lpr mice. That simultaneous studies by our group in NZB/NZW F1 [2], MRL-lpr/ lpr [2], and NZM.2410 (our unpublished data) models of lupus also found similar beneficial effects of treatment with an ACE inhibitor underscores the role of the reninangiotensin system in the pathogenesis of lupus nephritis. Renal protection in both studies appears to involve pathways that do not influence serum autoantibody levels or renal immune complex deposition [1, 2]. In our study, a selective reduction in chronic lesion scores that represent renal fibrosis, but not in the glomerular activity scores that mostly represent glomerular inflammation in NZB/NZW F1 mice, suggests that the protection against lupus nephritis probably involves mechanisms that cause tissue fibrosis. In that regard, type 2 cytokines that we have recently found to promote glomerulosclerosis [3] are consistently reduced in animals treated with the ACE inhibitor. TGFb1 and TGF-b2 isoforms were also selectively reduced in certain locations in the kidneys of treated mice [2]. Additionally, Perez ´ de Lema et al [1] found that glomerular cellularity and renal expression of chemokines such as CCL4 and CCL2 were reduced in animals treated with angiotensin inhibitors. That these authors did not find a reduction in inflammatory cell infiltrates in renal interstitium of the treated animals [1] suggests that modulation of inflammation is less likely to the primary mechanism responsible for renal protection in this system. In
a previous study, MCP-1/CCL2 induced a concentrationdependent increase in TGF-b by activated fibroblasts [4], suggesting the possibility of indirect regulation of collagen synthesis by MCP-1/CCL2 via TGF-b. Thus, we envision a scenario where type 2 cytokines such as IL-4, chemokines such as MCP-1/CCL2, and growth factors such as TGF-b orchestrate to assemble a network that promotes tissue fibrosis and causes chronic lupus nephritis. Understanding mechanisms involved in the regulation and counter-regulation of this network will have significant implications for the prevention of end-stage renal disease. RAM R. SINGH
Cincinnati, Ohio Correspondence to Ram Raj Singh, M.D., Professor of Medicine, 231 Albert Sabin Way, MSB Room 7464, Cincinnati, OH 45267-0563. E-mail: [email protected]
REFERENCES 1. PEREZ DE LEMA G, DE WIT C, NIETO E, et al: Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice. J Pharmacol Exp Ther 307:275–281, 2003 2. DE ALBUQUERQUE DA, SAXENA V, ADAMS DE, et al: An ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2 isoforms in murine lupus nephritis. Kidney Int 65:846–859, 2004 3. SINGH RR, SAXENA V, ZANG S, et al: Differential contribution of IL4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol 170:4818–4825, 2003 4. GHARAEE-KERMANI M, DENHOLM EM, PHAN SH: Costimulation of fibroblast collagen and transforming growth factor beta 1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 271:17779–17784, 1996