Renal Damage In Lupus Nephritis Research Articles

Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice

Deposition of immune complexes in the glomerulus leads to irreversible renal damage in lupus nephritis (LN), of which podocyte malfunction arises earlier. Fasudil, the only Rho GTPases inhibitor approved in clinical settings, possesses well-established renoprotective actions; yet, no studies addressed the amelioration derived from fasudil in LN. To clarify, we investigated whether fasudil exerted renal remission in lupus-prone mice. In this study, fasudil (20mg/kg) was intraperitoneally administered to female MRL/lpr mice for 10weeks. We report that fasudil administration swept antibodies (anti-dsDNA) and attenuated systemic inflammatory response in MRL/lpr mice, accompanied by preserving podocyte ultrastructure and averting immune complex deposition. Mechanistically, it repressed the expression of CaMK4 in glomerulopathy by preserving nephrin and synaptopodin expression. And fasudil further blocked cytoskeletal breakage in the Rho GTPases-dependent action. Further analyses showed that beneficial actions of fasudil on the podocytes required intra-nuclear YAP activation underlying actin dynamics. In addition, in vitro assays revealed that fasudil normalized the motile imbalance by suppressing intracellular calcium enrichment, thereby contributing to the resistance of apoptosis in podocytes. Altogether, our findings suggest that the precise manners of crosstalks between cytoskeletal assembly and YAP activation underlying the upstream CaMK4/Rho GTPases signal in podocytes is a reliable target for podocytopathies treatment, and fasudil might serve as a promising therapeutic agent to compensate for the podocyte injury in LN.

Excessive IL-15 promotes cytotoxic CD4 + CD28− T cell-mediated renal injury in lupus nephritis

BackgroundPatients with systemic lupus erythematosus (SLE) are highly susceptible to infection and cardiovascular events, suggesting that chronic antigenic stimulation may accelerate premature aging in SLE patients. Premature aging in SLE is often accompanied with the expansion of cytotoxic CD4 + CD28−T cells. Damage caused by CD4 + CD28− T cells enhances the progressive aging of the tissue function and loss of organism’s fitness. The high serum level of IL-15 has been implicated in the pathogenesis of SLE, but its role in CD4 + CD28−T cell-mediated cytotoxicity in nephritic SLE remains unclear. The aim of this study was to investigate the effect of IL-15 on functional properties and associated renal damage of cytotoxic CD4 + CD28− T cell in lupus nephritis (LN).ResultsFlow cytometry showed that the number of circulating innate-like CD4 + CD28− T cells was increased in patients with nephritic SLE. Immunofluorescence showed CD4 + CD28− T cell infiltration in the kidney of LN patients, which was correlated with multiple clinicopathological features including estimated glomerular filtration rate (eGFR), proteinuria, the proportion of glomerulosclerosis and the degree of renal chronicity. In addition, a high level of IL-15 and IL15-expressing macrophage infiltration was detected in the periglomerular and intraglomerular tissues of LN patients, which enhanced the innate features, cytokine secretion and migratory capability of CD4 + CD28− T cells, and finally exerted direct TCR-independent cytotoxicity on glomerular endothelial cells in an IL-15-dependent manner in vitro.ConclusionOur study demonstrated that excessive IL-15 potentially promoted cytotoxic CD4 + CD28− T cell-mediated renal damage in LN. This finding may provide new insights into the potential association of premature aging and tissue damage in LN.

MiR-384 is associated with renal damage in lupus nephritis via regulation of TET3 expression

Purpose: To investigate the correlations between miR-384 expression and renal damage in lupus nephritis (LN).Methods: Lupus nephritis and normal tissues were collected during surgery. The relative miR-384 expression was evaluated by extracting RNA and performing quantitative real time PCR (qRT-PCR) assays. Expression of ten-eleven translocation (TET3) mRNA and protein were measured by qRT-PCR and western blotting, respectively. The 24-h urine protein, serum complement C3, and serum creatinine were determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. TargetScan and luciferase assays were used to validate the binding site for miR-384 and its target mRNA. Relationships among miR-384, TET3, and renal damage were analyzed by Spearman rank-order correlation coefficients.Results: MiR-384 expression increased in LN tissues and was positively correlated with the activity index (AI) and chronicity index of LN, whereas miR-384 expression and serum complement C3 were negatively correlated. Positive correlations were observed between miR-384 expression and 24-h urine protein, serum creatinine, and systemic lupus erythematosus disease AI. TargetScan and luciferaseassays indicated that the TET3 3′-UTR was the direct target of miR-384. MiR-384 upregulation inhibited TET3 mRNA and protein expression, and was negatively associated with renal damage in LN.Conclusion: MiR-384 upregulation contributes to renal damage in LN by targeting the 3′-UTR of TET3 mRNA, suggesting that miR-384 is a potential biomarker and therapeutic target in LN.
 Keywords: MiR-384, Renal damage, Lupus nephritis, Ten-eleven translocation, TET3

Predictors of renal damage in systemic lupus erythematous patients: data from a multiethnic, multinational Latin American lupus cohort (GLADEL)

AimA decrease in proteinuria has been considered protective from renal damage in lupus nephritis (LN), but a cut-off point has yet to be established. The aim of this study was...

Serum uric acid as a sensitive concordant marker with lupus nephritis and new onset of renal damage: a prospective cohort study.

The objectives of this study are to assess serum different uric acid levels among systemic lupus erythematosus patients with or without active lupus nephritis in comparison to healthy controls and to study the relation of baseline uric acid levels to the development of new-onset renal damage in lupus nephritis. This is a case-control study followed by a prospective cohort of systemic lupus erythematosus (SLE) patients. Three groups were included; all were having normal kidney function, 25 SLE patients with recently diagnosed active lupus nephritis (LN), 26 SLE patients without LN, and 38 healthy controls. Serum uric acid (SUA)and serum creatinine were done for all groups; for SLE patients, 24-h protein in the urine, urinalysis, C3, C4 levels, anti-DNA, anti-ENA antibodies, SLE Disease Activity Index (SLEDAI), and SLICC/ACR damage index (SDI) evaluation were also calculated. Follow-up was done with clinical and laboratory assessment including SUA, with SLEDAI and SDI evaluation. Serum uric acid was significantly higher in SLE patients with active LN than the other two groups (p < 0.05), a cutoff value of serum uric acid associated with lupus nephritis onset was 0.41 mmol/L with a sensitivity of 58% and specificity of 100%, however, C3 and C4 showed very low sensitivity and specificity. During follow-up, all patients with LN with baseline serum uric acid ≥ 0.52 mmol/L were associated with new-onset renal damage within 43 months. High-serum uric acid levels showed a significant association with lupus nephritis onset and new onset of renal damage. Key Points • Serum uric acid is a cheap, rapid, and popular test available in most of the worldwide laboratories; its higher levels showed a significant association with lupus nephritis onset and new onset of renal damage • The current work is the largest study done on lupus nephritis with strict control to the confound risk factors that are associated with the increase of the uric acid levels; moreover, it is the first study to assess such relation in Saudi population • Uric acid could have a role in the pathogenesis of lupus nephritis patients and consequent renal damage.

JAK/STAT signaling controls the fate of CD8+CD103+ tissue-resident memory T cell in lupus nephritis

Autoimmune mediated inflammation and renal damage in lupus nephritis (LN) depends partly on the infiltration of lymphocytes in glomeruli and renal interstitium. Here we identified a population of CD8+ T cells with a CD103+-phenotype in the healthy kidneys of human and mouse. These cells were typically CD69+CD103+ tissue-resident memory T cells (TRM) in the kidney. CD8+ TRM cells were expanded in the kidneys of patients with LN or MRL/lpr mice. The expansion of renal CD8+ TRM cells correlated significantly with kidney disease activity. These cells were active in producing cytokines, perforin and granzyme B in the kidney of MRL/lpr mice. Importantly, renal CD8+ TRM cells underwent proliferation and self-renewal to maintain a stable TRM pool in the kidney of MRL/lpr mice, contributing to renal inflammation and damage. JAK/STAT signaling in the MRL/lpr mice was required for renal TRM self-renewal as well as maintenance of effector functions. Targeting JAK/STAT signaling by tofacitinib effectively suppressed effector functions and impaired the survival of renal TRM cells in the kidney, contributing to improved kidney function in MRL/lpr mice. These results provided evidences that renal CD8+ TRM cells play a role in the pathogenesis of LN. They could serve as a therapeutic target for LN.

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

Introduction: Lupus nephritis (LN) is a substantial manifestation of systemic lupus erythematosus (SLE). HDAC6 is overexpressed in various kidney diseases, and its inhibition slows kidney injury progression. Urinary TFF3 increases in chronic kidney diseases (CKDs) and may be associated with patient’s outcome. Objectives: This study aimed to examine the relationship between renal HDAC6 and TFF3 proteins expression and with clinicopathologic characteristics and outcome of LN. Patients and Methods: HDAC6 and TFF3 proteins’ expression was immunohistochemically detected in 56 cases of LN. They were correlated to patients’ age, gender, urinary 24 hours protein and serum creatinine levels at baseline and during follow up. Additionally, they were correlated to LN classes, activity index (AI) and chronicity index (CI) and relapse free survival (RFS). Results: HDAC6 overexpression was significantly associated with serum creatinine and 24 hours proteinuria levels at baseline (P = 0.041 and P =0.026 respectively) and during follow up (P &lt; 0.001). It was associated with AI and CI of class III and IV LN (P = 0.047 and 0.003 respectively). TFF3 overexpression was associated with higher serum creatinine and more proteinuria at baseline (P = 0.015 and 0.001 respectively) and during follow up (P &lt; 0.001). It was significantly associated with higher CI (P = 0.001). Both markers were associated with shorter RFS (P &lt; 0.001). Conclusion: HDAC6 and TFF3 proteins are associated with clinicopathologic features of renal damage in LN. They are reliable predictors of patients’ RFS, which makes them good candidates for risk stratification of patients and targeted therapy.

Chloroquine attenuates TLR3/IFN-β signaling in cultured normal human mesangial cells: A possible protective effect against renal damage in lupus nephritis

Background: Chloroquine has been reported to protect against renal damage in lupus nephritis (LN); however, its detailed mechanism in glomerular inflammation remains unclear. Upregulation of the type-I interferon (IFN) system plays a pivotal role in LN pathogenesis, therefore, we examined whether chloroquine inhibits toll-like receptor 3 (TLR3)/IFN-β signaling in cultured normal human mesangial cells (MCs).Methods: We examined chloroquine effect on the representative TLR3/IFN-β-signaling axis, TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 in MCs treated with polyinosinic-polycytidylic acid (poly IC), a synthetic viral dsRNA analog and analyzed the expression of these molecules using reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Furthermore, we subjected MCs to RNA interference against NF-κB p65.Results: Pretreatment of cells with chloroquine attenuated IFN-β, RIG-I and CCL5 expression and phosphorylation of STAT1 induced by poly IC, but not IFN-β-induced phosphorylation of STAT1 and RIG-I expression induced by IFN-β. Knockdown of p65 inhibited the poly IC-induced IFN-β expression, and chloroquine pretreatment decreased the nuclear poly IC-induced translocation of NF-κB p65 in MCs.Conclusion: These results suggest that chloroquine attenuates mesangial TLR3 signaling in the early phase of NF-κB activation. Considering that TLRs/type-I IFNs signaling is implicated in LN pathogenesis, our results may further support regional renoprotective effects of chloroquine in treating LN.

The Pathogenesis of Lupus Nephritis.

Lupus nephritis is a serious potential feature of systemic lupus erythematous (SLE). Though SLE typically cycles through periods of flares and remission, patients often eventually succumb to end-stage kidney or cardiovascular damage. This review of the pathogenesis of lupus nephritis examines the role of the complement cascade; the significance of autoantibodies, the breaking of tolerance, and the implications of altered apoptosis in breaking tolerance; and the contributions of adaptive immunity and cross-talk with the innate immune system in driving renal damage. Delineation of basic mechanisms underlying the development of acute and chronic renal damage in lupus nephritis can result in the continued development of more specific and effective treatments.

Mechanisms of progression of renal damage in lupus nephritis: pathogenesis of renal scarring.

Lupus nephritis results from an acute inflammatory and immunological response to renal immune complex deposition. The acute response is characterized by activation of circulating leukocytes and renal parenchymal cells, triggering the production of pro-inflammatory cytokines and growth factors. In all too many cases, this response is followed by a chronic response, which is characterized by excessive deposition of collagen and other extracellular matrix macromolecules and the development of end-stage renal disease. Mechanisms underlying this chronic response in progressive renal disease are not adequately defined. In this overview, potential roles of reactive oxygen species (ROS) generation and transforming growth factor-beta (TGF-beta) production in the pathogenesis of lupus nephritis are considered. ROS and TGF-beta may be key elements of a pathway leading to persistent and excessive matrix deposition in progressive lupus nephritis. Further studies to define the role of this pathway in lupus nephritis may lead to the development of additional, more specific therapeutic targets to prevent progression of renal disease.