Interleukin-11 Reduces Renal Injury and Glomerular NF-Kappa B Activity in Murine Experimental Glomerulonephritis

Lai, Ping-Chin; Smith, Jennifer; Bhangal, Gurjeet; Chaudhry, Kaleem; Chaudhry, Afzal; Keith, James C.; Tam, Frederick W.K.; Pusey, Charles D.; Cook, H. Terence

doi:10.1159/000087938

Cited by 18 publications

(9 citation statements)

References 61 publications

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“…There is in vivo evidence that IL-11 treatment enhanced recipient survival by suppressing cytokine production. [33][34][35] This anti-inflammatory effect is mediated by its ability to block the nuclear translocation of NFkB. In our siCD40-treated grafts, NFkB expression was downregulated and its translocation to the nucleus was blocked.…”

Section: Local Silencing Of Cd40 Changes Rejection Pattern E Ripoll Ementioning

confidence: 69%

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

et al. 2011

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The humoral branch of the immune response has an important role in acute and chronic allograft dysfunction. The CD40/CD40L costimulatory pathway is crucial in B-and T-alloresponse. Our group has developed a new small interfering RNA (siRNA) molecule against CD40 that effectively inhibits its expression. The aim of the present study was to prevent rejection in an acute vascular rejection model of kidney transplant by intra-graft gene silencing with anti-CD40 siRNA (siCD40), associated or not with sub-therapeutic rapamycin. Four groups were designed: unspecific siRNA as control; sub-therapeutic rapamycin; siCD40; and combination therapy. Long-surviving rats were found only in both siCD40-treated groups. The CD40 mRNA was overexpressed in control grafts but treatment with siCD40 decreased its expression. Recipient spleen CD40+ B-lymphocytes were reduced in both siCD40-treated groups. Moreover, CD40 silencing reduced donor-specific antibodies, graft complement deposition and immune-inflammatory mediators. The characteristic histological features of humoral rejection were not found in siCD40-treated grafts, which showed a more cellular histological pattern. Therefore, the intra-renal effective blockade of the CD40/CD40L signal reduces the graft inflammation as well as the incidence of humoral vascular acute rejection, finally changing the type of rejection from humoral to cellular. Gene Therapy (2011) 18, 945-952;

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Section: Local Silencing Of Cd40 Changes Rejection Pattern E Ripoll Ementioning

confidence: 69%

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

et al. 2011

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“…As AGT is a well known drug target, and is known to be expressed in the kidney, as well as liver, lung, heart, and parts of the brain, AGT became our top candidate for validation. PRKRIP1 is also known to be well expressed in kidney and is induced by IL11 (21). IL11 can play a therapeutic role in reducing glomerular injury in mouse models of glomerulonephritis (22).…”

Section: Resultsmentioning

confidence: 99%

Protein Microarrays Discover Angiotensinogen and PRKRIP1 as Novel Targets for Autoantibodies in Chronic Renal Disease

Butte

Sigdel

Wadia

et al. 2011

Molecular & Cellular Proteomics

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Biomarkers for early detection of chronic kidney disease are needed, as millions of patients suffer from chronic diseases predisposing them to kidney failure. Protein microarrays may also hold utility in the discovery of autoantibodies in other conditions not commonly considered auto-immune diseases. We hypothesized that proteins are released as a consequence of damage at a cellular level during end-organ damage from renal injury, not otherwise recognized as self-antigens, and an adaptive humoral immune response to these proteins might be detected in the blood, as a noninvasive tracker of this injury. The resultant antibodies (Ab) detected in the blood would serve as effective biomarkers for occult renal injury, enabling earlier clinical detection of chronic kidney disease than currently possible, because of the redundancy of the serum creatinine as a biomarker for early kidney injury. To screen for novel autoantibodies in chronic kidney disease, 24 protein microarrays were used to compare serum Ab from patients with chronic kidney disease against matched controls. From a panel of 38 antigens with increased Ab binding, four were validated in 71 individuals, with (n ‫؍‬ 50) and without (n ‫؍‬ 21) renal insufficiency. Significant elevations in the titer of novel auto-Ab were noted against angiotensinogen and PRKRIP1 in renal insufficiency. Current validation is underway to evaluate if these auto-Ab can provide means to follow the evolution of chronic kidney disease in patients with early stages of renal insufficiency, and if these rising titers of these auto-Ab correlate with the rate

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“…The relevance of fibrinogen deposition after human kidney transplantation was previously demonstrated [49]. Besides these transplantation models, the substantial contribution of fibrinogen was characterized in different models of glomerulonephritis [50,51,52,53]. The significantly induced fibrinogen mRNA synthesis after allogeneic transplantation might be regarded as a hint for an ongoing contribution of fibrinogen to allograft damage in an acute rejection model.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 in Experimental Kidney Transplantation: Early Mediator of Endogenous Danger Signals

Bergler¹,

Hoffmann²,

Bergler³

et al. 2012

Nephron Exp Nephrol

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The role of toll-like receptors (TLRs) has been described in the pathogenesis of renal ischemia/reperfusion injury, but data on the expression and function of TLR4 during renal allograft damage are still scarce. We analyzed the expression of TLR4 in an experimental rat model 6 and 28 days after allogeneic kidney transplantation in comparison to control rats and rats after syngeneic transplantation. On day 6, a significant induction in TLR4 expression – restricted to the glomerular compartment – was found in acute rejecting allografts only. TLR4 expression strongly correlated with renal function, and TLR4 induction was accompanied by a significant increase in CC chemokine expression within the graft as well as in urinary CC chemokine excretion. TLR4 induction may be caused by an influx of macrophages as well as TLR4-expressing intrinsic renal cells. Fibrinogen deposition in renal allografts correlated with renal TLR4 expression and may act as a potent stimulator of chemokine release via TLR4 activation. This study provides, for the first time, data about the precise intrarenal localization and TLR4 induction after experimental kidney transplantation. It supports the hypothesis that local TLR4 activation by endogenous ligands may be one pathological link from unspecific primary allograft damage to subsequent chemokine release, infiltration and activation of immune cells leading to deterioration of renal function and induction of renal fibrosis.

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Interleukin-11 Reduces Renal Injury and Glomerular NF-Kappa B Activity in Murine Experimental Glomerulonephritis

Cited by 18 publications

References 61 publications

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

Protein Microarrays Discover Angiotensinogen and PRKRIP1 as Novel Targets for Autoantibodies in Chronic Renal Disease

Toll-Like Receptor 4 in Experimental Kidney Transplantation: Early Mediator of Endogenous Danger Signals

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