Effects of Rapamycin on Active Heymann Nephritis

Naumovic, Radomir; Jovović, Djurdjica; Basta-Jovanović, Gordana; Miloradović, Zoran; Mihailović-Stanojević, Nevena; Aleksic, Tamara; Jovanović, D

doi:10.1159/000103918

Cited by 22 publications

(16 citation statements)

References 42 publications

(34 reference statements)

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“…The results of the present study, as well as those of others utilizing animal models of membranous nephropathy [30] and reduced renal mass [31], indicate that rapamycin is a promising agent in treating proteinuric nephropathy. The safety of using rapamycin in clinical practice to treat patients with proteinuric nephropathy, however, is more controversial.…”

Section: Discussionsupporting

confidence: 79%

Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy

Lui¹,

Tsang²,

Chan³

et al. 2008

Am J Nephrol

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Background: Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive glomerulosclerosis and tubulointerstitial fibrosis. Methods: Adriamycin nephropathy was induced in Balb/c mice by a single intravenous injection of adriamycin. The mice were treated orally with either saline or rapamycin, beginning at the time of adriamycin injection or rapamycin starting 1 week after adriamycin injection. The mice were sacrificed 6 weeks after adriamycin injection. Results: Saline-treated mice developed massive proteinuria and impaired renal function. Kidney sections from saline-treated mice showed marked focal segmental glomerulosclerosis, tubular dilation with protein cast deposition, interstitial fibrosis, and numerous infiltrating macrophages and T lymphocytes. The intrarenal expression of Collagen I and RANTES was also increased. In contrast, both groups of rapamycin-treated mice had markedly reduced proteinuria and preserved renal function, with only mild histological abnormalities. The intrarenal expression of Collagen I and RANTES was reduced, concomitant with a significant reduction in interstitial inflammatory cell infiltration. Conclusions: Rapamycin is effective in attenuating the glomerular and tubulointerstitial abnormalities in adriamycin nephropathy_.The beneficial effects of rapamycin are mediated, at least in part, through reduced RANTES expression and inflammatory cell infiltration.

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Section: Discussionsupporting

confidence: 79%

Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy

Lui¹,

Tsang²,

Chan³

et al. 2008

Am J Nephrol

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“…Rapamycin, an inhibitor of mTOR signaling, regulates glomerular function both in vitro and in vivo 18 -20 and exhibits renoprotective effects in many animal models of renal damage. 20,32,33 Concordantly, pretreatment of isolated glomeruli with rapamycin dose-dependently ameliorates the effects of PS ( Figure 5A), indicating that mTOR signaling is necessary for PS injury.…”

Section: Can and Synpo Are Critical Early Regulators Of Glomerular Bamentioning

confidence: 62%

Calcium Mediates Glomerular Filtration through Calcineurin and mTORC2/Akt Signaling

Vassiliadis

Bracken

Matthews

et al. 2011

Journal of the American Society of Nephrology

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Alterations to the structure of the glomerular filtration barrier lead to effacement of podocyte foot processes, leakage of albumin, and the development of proteinuria. To better understand the signaling pathways involved in the response of the glomerular filtration barrier to injury, we studied freshly isolated rat glomeruli, which allows for the monitoring and pharmacologic manipulation of early signaling events. Administration of protamine sulfate rapidly damaged the isolated glomeruli, resulting in foot process effacement and albumin leakage. Inhibition of calcium channels and chelation of extracellular calcium reduced protamine sulfateinduced damage, suggesting that calcium signaling plays a critical role in the initial stages of glomerular injury. Calcineurin inhibitors (FK506 and cyclosporine A) and the cathepsin L inhibitor E64 all inhibited protamine sulfate-mediated barrier changes, which suggests that calcium signaling acts, in part, through calcineurin-and cathepsin L-dependent cleavage of synaptopodin, a regulator of actin dynamics. The mTOR inhibitor rapamycin also protected glomeruli, demonstrating that calcium signaling has additional calcineurinindependent components. Furthermore, activation of Akt through mTOR had a direct role on glomerular barrier integrity, and activation of calcium channels mediated this process, likely independent of phosphoinositide 3-kinase. Taken together, these results demonstrate the importance of calcium and related signaling pathways in the structure and function of the glomerular filtration barrier.

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“…The mTOR pathway also affects the development and progression of immunologically mediated forms of CKD, such as membranous glomerulopathy (passive and active forms of Heymann nephritis) (65,107), mesangiocapillary anti-Thy-1 nephritis (108,109), lupus (105–107,110,111), and antiglomerular basement membrane GN (112). Whereas mTOR inhibitors usually exert beneficial effects consistent with their immunosuppressive and anti-inflammatory actions, they can be detrimental under certain conditions because of downregulation of vascular endothelial growth factor (VEGF).…”

Section: Mtor Fibrosis Chronic Kidney Disease and Animal Models Of mentioning

confidence: 99%

Prospects for mTOR Inhibitor Use in Patients with Polycystic Kidney Disease and Hamartomatous Diseases

Torres

Boletta

Chapman

et al. 2010

Clinical Journal of the American Society of Nephrology

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Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.

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Effects of Rapamycin on Active Heymann Nephritis

Cited by 22 publications

References 42 publications

Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy

Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy

Calcium Mediates Glomerular Filtration through Calcineurin and mTORC2/Akt Signaling

Prospects for mTOR Inhibitor Use in Patients with Polycystic Kidney Disease and Hamartomatous Diseases

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