Renin-Angiotensin System Blockade Is Renoprotective in Immune Complex–Mediated Glomerulonephritis

Abstract

Blockade of the renin-angiotensin system is renoprotective in a variety of chronic nephropathies, but the direct effect of such treatment in active, immune complex-mediated glomerulonephritis is unknown. This study investigated the short-and long-term effects of an angiotensin-converting enzyme inhibitor (enalapril) and an angiotensin II type 1 receptor blocker (losartan) in thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop mixed cryoglobulinemia and severe cryoglobulinemia-associated membranoproliferative glomerulonephritis. Enalapril and losartan each reduced hypertension, proteinuria, glomerular extracellular matrix deposition, and mesangial cell activation in TSLPtg mice. These renoprotective effects were not observed with hydralazine treatment, despite a similar antihypertensive effect. Treatment with enalapril or losartan also decreased renal plasminogen activator inhibitor-1 in TSLPtg mice, assessed by immunohistochemistry and quantitative real-time reverse transcriptase-PCR. None of the treatments affected immune complex deposition or macrophage infiltration. Overall, enalapril-and losartan-treated TSLPtg mice survived significantly longer than untreated TSLPtg mice. These studies demonstrate that angiotensin blockade may provide renoprotective benefits, independent of its BP-lowering effect, in the treatment of active immune complex-mediated glomerulonephritis. Effective treatment for most forms of glomerulonephritis remains an elusive goal. In cases of immune complex-mediated glomerulonephritis, specific treatment options are often limited to immunosuppressive agents such as glucocorticoids and cytotoxic agents, which have the dual burdens of limited efficacy and multiple severe toxicities. An exception is the case of membranoproliferative glomerulonephritis (MPGN) consequent to cryoglobulinemia associated with longstanding hepatitis C virus (HCV) infection. In that setting, antiviral therapy directed at the underlying HCV infection, typically IFN based, can cause remission of cryoglobulinemia and the MPGN if HCV viremia is eradicated. 1 Unfortunately, this occurs in only a minority of patients with this disorder, and other efficacious therapies either have not been identified or have been tested in only a small number of patients.In recent years, blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) has shown compelling renoprotective effects in chronic renal diseases of humans and animal models. 2,3 Most experimental studies of RAS blockade have used chronic nephropathy models resulting from diabetes, 4,5 hypertension, 6,7 nephrotoxicity, 8 reduction of renal

Pro-inflammatory role of angiotensin II in mercuric chloride-induced nephropathy in rats

“…This indicated to us that ICAM-1, ED-1, or iNOS expressions were, in part, up-regulated by endogenous Ang II. In this regard, the blocking of Ang II was associated with diminished expression of pro-inflammatory molecules, an outcome that has been reported in other renal and vascular pathologies (Guo et al, 2008;Marchesi et al, 2008;Hayashi et al, 2010).…”

“…Rats in the Losartan (Cozaar, Merck & Co., Whitehouse Station, NJ) group received this antagonist of AT-1 receptors (angiotensin II receptor type-1) at 30 mg Losartan/kg BW daily by gastric gavage (Abdi and Johns, 1997). Rats in the Enalapril (Renitec, Merck) group received this inhibitor of angiotensin I converting enzyme at 30 mg Losartan/kg BW daily by gavage (Guo et al, 2008). Rats in the nondrug-treated group received distilled water only daily by gavage.…”

Imatinib

“…To highlight the immunomodulatory role of imatinib, the same thymic stromal lymphopoietin tg mouse model was treated with angiotensinconverting enzyme inhibition or angiotensin-receptor blocker therapy alone and showed no improvement in markers of immunologic activation. 56 Imatinib also inhibited T cell infiltration in mouse models of anti-glomerular basement membrane (GBM) disease and chronic allograft nephropathy. 57,58 Macrophage infiltration was decreased in models of chronic allograft nephropathy, streptozotocin-induced diabetic nephropathy, LN, and anti-GBM disease treated with imatinib whereas nilotinib Figure 2.…”

Deletion of Activating Fcγ Receptors Does Not Confer Protection in Murine Cryoglobulinemia-Associated Membranoproliferative Glomerulonephritis

“…Glomerular tuft area and the proportion of the glomerular area occupied by black silver methenamine-stained matrix or stained by antibodies to type IV collagen, or the proportion occupied by cells expressing ␣-SMA, Mac-2, or CD3 were quantified as previously described. 10,15,16 In Masson's trichrome-stained kidney tissue, ICs are stained brown-pink and can be differentiated from cells and extracellular matrix. Accumulations of stained ICs in glomeruli were morphometrically quantified as the proportion of IC-stained area in glomerular tuft area in TSLPtg and TSLPtg/FcR␥ Ϫ/Ϫ mice.…”

“…As previously described, the liver and lung inflammation was scored semiquantitatively on a scale of 0 to 3: 0, no inflammation; 1, mild; 2, moderate; 3, severe, with regard to the extent and density of leukocytic infiltration. 15,17 All data are expressed as mean Ϯ SEM. Statistical analysis of the data for multiple groups was performed by TSLPtg mice developed typical features of cryoglobulin-associated MPGN as described previously.…”