Brad H Rovin

The Ohio State University, Columbus, Ohio, United States

Are you Brad H Rovin?

Claim your profile

Publications (163)1031.21 Total impact

  • Nephrology Dialysis Transplantation 11/2014; · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypertension is a common comorbidity in patients with chronic kidney disease (CKD). We reported earlier that oral anticoagulants, including warfarin and dabigatran, may induce acute kidney injury. No effects of oral anticoagulants on blood pressure (BP) have been previously reported. The aim of this study was to examine in detail the relationship of anticoagulant therapy and BP in rats.
    American Journal of Hypertension 07/2014; · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We present a unique case in which tubular epithelial crystalline deposits were initially overlooked on renal biopsy and thus the patient did not receive treatment for over a decade. Despite this, he had no progression of his renal disease. This case prompted a review of the literature to investigate how other patients with this rare renal disease have been treated, and what their outcomes were. Our review of the literature shows that for many patients with κ-light chain crystalline proximal tubulopathy and a plasma cell dyscrasia, chemotherapy does not seem to drastically improve renal function and may not be necessary in the absence of multiple myeloma. Watchful waiting may, in fact, be more beneficial.
    Clinical nephrology. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Purpose:Lupus nephritis (LN) is frequently associated with a poor long-term prognosis. Current non-invasive blood and urine tests do not reliably predict the course of LN. The objective of this study was to evaluate the performance of candidate urine biomarkers in predicting future kidney function in adults and children with LN. The biomarker candidates studies were liver-type fatty acid binding protein (L-FABP), albumin (Alb), monocyte chemoattractant protein 1 (MCP-1), Uromodulin, Transferrin and Hepcidin.Methods:L-FABP, Alb, MCP-1, Uromodulin, Transferrin and Hepcidin were measured by ELISA in urine from 70 adults and 42 children collected at the time of enrollment into prospective observational LN cohorts. Urine analytes were normalized to urine creatinine and logarithmically transformed. The association of each analyte to renal function loss (RFL), defined as a sustained increase of ≥25% in serum creatinine (SCr; adults) or a decrease in eGFR of ≥20% (children), was determined using a fixed effect model after adjusting for the age group (adult vs. child). In addition, the results were confirmed using Wilcoxon Rank Sum tests. Logistical models were used to predict the presence of RFL using each biomarker or a combination of the biomarkers. Biomarker performance in predicting RFL was assessed as the area under a ROC curve (AUC) corresponding to the logistical model.Results:13 children and 22 adults had RFL during the mean follow-up period of 6.1 months and 60 months, respectively. Overall patients with RFL showed significantly higher levels ALB than those without RFL (p < 0.05, 1). In addition, the levels of L-FABP, MCP-1, and Transferrin were also marginally higher in RFL (p-values < 0.1). The AUC using the combination of urine L-FABP, Alb, MCP-1 and Utransferrin was 0.66, slightly higher than those using any single biomarker as the predictor (ranging from 0.52–0.63).Table 1. Patient typeBiomarker/Cr$Renal function loss$Preserved renal function$p (Fixed effect model/Wilcoxon) N3577– LFABP1.75 ± 1.581.17 ± 1.620.084 / 0.066 Albumin5.58 ± 2.314.46 ± 2.190.017 / 0.030 MCP-15.77 ± 1.634.89 ± 2.450.064 / 0.034 UROMODULIN2.04 ± 1.302.14 ± 1.140.683 / 0.644 UTRANSFERRIN2.27 ± 2.271.49 ± 1.980.073 / 0.070All patients with LNHEPCIDIN3.85 ± 1.153.57 ± 1.670.378 / 0.656 N2248– LFABP1.69 ± 1.261.28 ± 1.690.326 / 0.229 Albumin5.90 ± 2.145.01 ± 2.010.100 / 0.147 MCP-15.98 ± 1.164.80 ± 2.700.061 / 0.057 UROMODULIN1.33 ± 1.061.65 ± 1.080.261 / 0.274 UTRANSFERRIN1.98 ± 1.781.41 ± 1.960.255 / 0.177Adults with LNHEPCIDIN3.80 ± 0.953.28 ± 1.710.197 / 0.368 N1329– LFABP1.84 ± 2.050.98 ± 1.500.136 / 0.218 Albumin5.05 ± 2.573.55 ± 2.210.060 / 0.116 MCP-15.38 ± 2.305.02 ± 2.020.634 / 0.402 UROMODULIN3.19 ± 0.682.96 ± 0.690.314 / 0.589 UTRANSFERRIN2.73 ± 2.941.64 ± 2.040.170 / 0.199Children with LNHEPCIDIN3.91 ± 1.454.02 ± 1.510.830 / 0.803Conclusion:Urine biomarkers L-FABP, Alb and MCP-1 are likely predictive to RFL. Other biomarkers such as Uromodulin, Transferrin and Hepcidin are markers of disease activity, but not predictive of RFL.
    Arthritis & Rheumatology. 03/2014; 66(S11).
  • Brad H Rovin, Samir V Parikh
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune complex accumulation in the kidney is the hallmark of lupus nephritis and triggers a series of events that result in kidney inflammation and injury. Cytotoxic agents and corticosteroids are standard of care for lupus nephritis treatment, but are associated with considerable morbidity and suboptimal outcomes. Recently, there has been interest in using novel biologic agents and small molecules to treat lupus nephritis. These therapies can be broadly categorized as anti-inflammatory (laquinamod, anti-tumor necrosis factor-like weak inducer of apotosis, anti-C5, and retinoids), antiautoimmunity (anti-CD20, anti-interferon α, and costimulatory blockers), or both (anti-interleukin 6 and proteasome inhibitors). Recent lupus nephritis clinical trials applied biologics or small molecules of any category to induction treatment, seeking short-term end points of complete renal response. These trials in general have not succeeded. When lupus nephritis comes to clinical attention during the inflammatory stage of the disease, the autoimmune stage leading to kidney inflammation will have been active for some time. The optimal approach for using novel therapies may be to initially target kidney inflammation to preserve renal parenchyma, followed by suppression of autoimmunity. In this review, we discuss novel lupus nephritis therapies and how they fit into a combinatorial treatment strategy based on the pathogenic stage.
    American Journal of Kidney Diseases 01/2014; · 5.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The kidney biopsy is the standard of care for diagnosis of lupus nephritis and remains necessary to ensure accurate diagnosis and guide treatment. Repeat biopsy should be considered when therapy modifications are necessary, as in cases with incomplete or no response, or when stopping therapy for those in remission. There are several promising biomarkers of kidney disorders; however, these markers need to be validated in a prospective clinical trial before being applied clinically. Molecular analysis may provide the information presently lacking from current evaluation of kidney disorders and may better inform on prognosis and treatment considerations.
    Rheumatic Disease Clinics of North America 01/2014; · 1.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal flares are common in lupus nephritis. The impact of flares on the development of CKD in lupus nephritis was examined. A retrospective analysis of prospectively collected data from the Ohio Systemic Lupus Erythematosus (SLE) Study was conducted to determine if renal flares predispose to new CKD or progression of preexisting CKD. Patients in the Ohio SLE Study were followed from 2001 to 2009, with a median follow-up of 6 years. For this analysis, patients with biopsy-proven lupus nephritis and at least 3 years of follow-up were included (n=56). Frequency and duration of renal flares were compared between patients who never developed CKD (n=29) and patients who developed new CKD (n=12) and between patients with preexisting but stable CKD (n=7) and patients who progressed (n=8). Groups were also combined into good (no CKD and stable CKD) or poor (new CKD and progressive CKD) for analysis. The new CKD group had more renal flares per year compared with the no CKD group (median=0.56 flares/yr [range=0-2] versus median=0 flares/yr [range=0-1.4]; P<0.001). Additionally, the poor outcome group had more renal flares per year compared with the good outcome group (median=0.50 flares/yr [range=0-2] versus median=0 flares/yr [range=0-1.4]; P<0.001). New or progressive CKD was not preferentially associated with nephritic compared with proteinuric renal flares. Logistic regression showed that spending more than 30% of time in renal flare (odds ratio, 20; 95% confidence interval, 4.6 to 91.3; P<0.001) and age>35 years (odds ratio, 69; 95% confidence interval, 6.3 to 753.6; P<0.001) were independent predictors of the combined end point of developing new or progressive CKD. All four subjects over 35 years of age that spent over 30% of time in renal flare had a poor outcome. In patients with lupus nephritis, the relative duration of renal flare is an independent predictor of incident and progressive CKD.
    Clinical Journal of the American Society of Nephrology 11/2013; · 5.07 Impact Factor
  • Annals of the rheumatic diseases 10/2013; · 9.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Glomerular disease is a complex and evolving topic. In evaluating a specific case it is not unusual for the clinician to ask: 'Am I missing something? Should I biopsy? When? Should I treat first, then biopsy?' This work, which is both evidence and experience based, is intended to address each of these concerns and many other issues relevant to the differential diagnosis of glomerular disease. Summary: The central approach is the use of diagnostic algorithms that are based on quantitative measures routinely obtained early in the course of the diagnostic evaluation. The algorithms are designed to be easy to navigate, systematic, and inclusive. Also provided is a detailed and prioritized list of recommended diagnostic testing, and the rationale for each test. Key Message: This work is intended to facilitate accurate diagnosis in the individual patient presenting with evidence of glomerular disease.
    American Journal of Nephrology 09/2013; 38(3):253-266. · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Excessive anticoagulation with warfarin can result in acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts in some patients, especially in those with chronic kidney disease (CKD). This condition was described as warfarin-related nephropathy (WRN). Recent evidence suggests that WRN-like syndromes are not confined to anticoagulation with warfarin, but may be seen with other anticoagulants, such as dabigatran. The aim of this study was to investigate dabigatran effects on kidney function in an animal model of CKD and possible pathogenic mechanisms of AKI. Control and 5/6 nephrectomy rats were treated with different doses of dabigatran and protease-activated receptor 1 (PAR-1) inhibitor SCH79797. Dabigatran resulted in changes in coagulation in rats similar to those in humans at 50 mg/kg/day. Dabigatran resulted in a dose-dependent increase in serum creatinine (Scr) and hematuria in both control and 5/6 nephrectomy rats. SCH79797 also increased Scr and hematuria, more prominent in animals with CKD. Morphologically, numerous RBC tubular casts were seen in 5/6 nephrectomy rats treated with either dabigatran or SCH79797 and only occasional RBC casts in control rats. Our data indicate that WRN represents part of a broader syndrome, anticoagulant-related nephropathy (ARN). ARN, at least partially, is mediated via PAR-1. Our findings suggest that not only CKD patients, but other patients as well, are at high risk of developing AKI if the therapeutic range of anticoagulation with dabigatran is exceeded. Close monitoring of kidney function in patients on dabigatran therapy is warranted.
    Nephrology Dialysis Transplantation 09/2013; · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Warfarin related nephropathy (WRN) occurs under conditions of over-anticoagulation with warfarin. WRN is characterized by glomerular hemorrhage with occlusive tubular red blood cell (RBC) casts and acute kidney injury (AKI). Herein we test the hypothesis that oxidative stress plays a role in the AKI of WRN. 5/6 nephrectomy rats were treated with either warfarin (0.04 mg/kg/day) alone or with 4 different doses of the antioxidant N-acetylcysteine (NAC). Also, tested was the ability of our NAC regimen to mitigate AKI in a standard ischemia/reperfusion model in the rat. Warfarin resulted in a 3-fold or greater increase in PT in each experimental group. Scr increased progressively in animals receiving only warfarin + vehicle. However, in animals receiving warfarin + NAC, the increase in Scr was lessened, starting at NAC 40 mg/kg/day, and completely prevented at NAC 80 mg/kg/day. NAC did not decrease hematuria or obstructive RBC casts, but mitigated acute tubular injury. Oxidative stress in the kidney was increased in animals with WRN and it was decreased by NAC. The NAC regimen used in the WRN model preserved kidney function in the ischemia/reperfusion model. Treatment with deferoxamine (iron chelator) did not affect WRN. No iron was detected in tubular epithelial cells. In conclusion, this work taken together with our previous work in WRN models shows that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The dominant mechanism of the AKI of WRN is tubular obstruction by RBC casts with increased oxidative stress in the kidney.
    AJP Renal Physiology 04/2013; · 4.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: New filtration markers, including β-trace protein (BTP) and β2-microglobulin (B2M), may, similar to cystatin C, enable a stronger prediction of mortality compared to serum creatinine-based estimated glomerular filtration rate (eGFRcr). We sought to evaluate these mortality associations in a representative sample of US adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 6,445 adults 20 years or older from the Third National Health and Nutrition Examination Survey (1988-1994) with mortality linkage through December 31, 2006. PREDICTORS: Serum cystatin C, BTP, and B2M levels and eGFRcr categorized into quintiles, with the highest quintile (lowest for eGFRcr) split into tertiles (subquintiles Q5a-Q5c). OUTCOMES: All-cause, cardiovascular disease, and coronary heart disease mortality. MEASUREMENTS: Demographic- and multivariable-adjusted Cox proportional hazard models. RESULTS: During follow-up, 2,392 deaths (cardiovascular, 1,079; coronary heart disease, 605) occurred. Levels of all 4 filtration markers were associated with mortality risk after adjusting for demographics (P trend < 0.02). Adjusted for mortality risk factors, compared to the middle quintile, the highest subquintiles for cystatin C (Q5c: HR, 1.94; 95% CI, 1.43-2.62), BTP (Q5c: HR, 2.14; 95% CI, 1.56-2.94), and B2M (Q5c: HR, 2.58; 95% CI, 1.96-3.41) were associated with increased all-cause mortality risk, whereas the association was weaker for eGFRcr (Q5c: HR, 1.31; 95% CI, 0.84-2.04). Associations persisted for the novel markers and not for eGFRcr at eGFRcr ≥60 mL/min/1.73 m(2). Trends were similar for cardiovascular disease and coronary heart disease mortality. LIMITATIONS: Single measurements of markers from long-term stored samples. CONCLUSIONS: The strong association of cystatin C level with mortality compared with serum creatinine estimates is shared by BTP and B2M. This supports the utility of alternative filtration markers beyond creatinine when improved risk prediction related to decreased GFR is needed.
    American Journal of Kidney Diseases 03/2013; · 5.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Kidney biopsy is a vital tool in the diagnosis of kidney disease. Although it has become a routine procedure, it is not complication-free. Some serious complications of percutaneous kidney biopsy include retroperitoneal hemorrhage and death. There is an increased belief that smaller biopsy needle size results in a lower complication rate. As renal pathologists, we witness an increased number of kidney biopsies performed with a small needle size (as low as gauge 22), which results in inadequate tissue sampling and often non-diagnostic biopsy results. Herein we report the diagnostic value of kidney biopsies according to the size of the biopsy needles. Methods: We performed kidney biopsies from nephrectomy specimens using biopsy needles of different sizes. Morphologic parameters were analyzed. Results: We found that biopsies performed by small needles (gauges 20 and 22) contain significantly lower numbers of glomeruli and blood vessels, which limits pathologic evaluation. Data from our institution do not show differences in kidney biopsy complication rates between 16- and 18-gauge needles. Conclusions: Our data indicate that small biopsy needles do not provide sufficient material for diagnosis, and they increase the likelihood for a repeat biopsy.
    American Journal of Nephrology 03/2013; 37(3):249-254. · 2.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective To study the level of high-sensitivity C-reactive protein (hsCRP) and its relationship with disease activity, damage, and cardiovascular risk factors in patients with systemic lupus erythematosus (SLE). Methods Consecutive patients who fulfilled ≥4 American College of Rheumatology criteria for SLE who did not have a concurrent infection were recruited. Blood was assayed for hsCRP level, and disease activity, organ damage of SLE, and cardiovascular risk factors were assessed. Linear regression analyses were performed for the relationship between hsCRP levels, SLE activity, damage, and cardiovascular risk factors. ResultsIn total, 289 patients were studied (94% women, mean ± SD age 39.0 ± 13.1 years, and mean ± SD SLE duration 7.8 ± 6.7 years). The mean ± SD Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 4.9 ± 5.6 and clinically active SLE was present in 122 patients (42%). The mean ± SD hsCRP level was 4.87 ± 12.7 mg/liter, and 28 patients with active SLE (23%) had an undetectable hsCRP level (3 mg/liter was significantly associated with male sex, long-term smoking, diabetes mellitus, a higher atherogenic index, and a history of arterial thrombosis. hsCRP levels correlated significantly with pulmonary and endocrine damage scores. ConclusionhsCRP was detectable in 77% of SLE patients with clinically active disease and correlated with SLEDAI scores, particularly in serositis and in the musculoskeletal and hematologic systems. Elevated hsCRP levels in SLE were associated with certain cardiovascular risk factors and a history of arterial thromboembolism.
    Arthritis Care & Research. 03/2013; 65(3).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our patient appears to represent a previously unrecognized variant of steroid-responsive minimal change disease (MCD)/focal and segmental glomerulosclerosis (FSGS) in which severe AKI developed even though the serum albumin was essentially normal and proteinuria was minimal. This would be a paradox because the AKI of MCD/FSGS is a manifestation of severe nephrotic syndrome. To explain this paradox, it is suggested that our patient is a rare variant of a phenomenon that is well documented in steroid-responsive MCD/FSGS, specifically, glomerular permeability to large molecules is increased (accounting for the proteinuria) but decreased to small molecules (accounting for the low glomerular filtration rate). Our patient promptly recovered kidney function on steroid therapy even though he had been oliguric and dialysis dependent for nearly 11 months. The possible pathophysiologic mechanisms for this remarkable presentation and outcome are discussed.
    Clinical nephrology 02/2013; · 1.23 Impact Factor
  • Xiaolan Zhang, Brad H Rovin
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Hepcidin is an iron regulatory protein mainly synthesized by the liver. Hepatocyte production of hepcidin is responsible for serum hepcidin, is responsive to body iron stores, and is critical for maintaining iron homeostasis. Monocytes and macrophages also express hepcidin, and in contrast to the liver, hepcidin expression is primarily regulated by inflammatory mediators and infectious agents. Monocyte and macrophage hepcidin is likely to be more important on a local rather than systemic level, contributes to host defense and may modulate inflammatory processes. This review summarizes recent findings and hypotheses on the relationship of hepcidin to the mononuclear phagocyte system.
    Biological Chemistry 02/2013; 394(2):231-8. · 2.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3+) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P=0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P=0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.Modern Pathology advance online publication, 18 January 2013; doi:10.1038/modpathol.2012.237.
    Modern Pathology 01/2013; · 6.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: In children and adults, Henoch-Schönlein purpura (HSP) has a characteristic clinical presentation that includes a purpuric lower extremity skin rash, IgA-dominant glomerulonephritis, and abdominal and joint pain. A similar clinical presentation can be seen in adults who have a systemic infection with methicillin-resistant Staphylococcus aureus. It is critically important to distinguish the IgAdominant glomerulonephritis of HSP from the IgA-dominant glomerulonephritis of staphylococcal infection, because HSP may need to be treated with corticosteroids and immunosuppressives, while Staphylococcus infection-associated glomerulonephritis requires antibiotics. Design: We searched our renal biopsy database for cases of Staphylococcus infection-associated IgA-dominant glomerulonephritis, to identify those with an HSP-like presentation. Their clinical, laboratory, and biopsy findings are reviewed. Results: Between 2004 and 2011, we identified 37 patients with culture-proven Staphylococcus infection-associated glomerulonephritis. Of these, 8 (22%) had an HSP-like presentation manifested by lower extremity purpuric skin rash. Mesangial IgA and C3 deposits were consistent findings on kidney biopsy. Crescents were uncommon. Four of the 8 patients received glucocorticoid (steroid) therapy for a presumed diagnosis of HSP. Renal function worsened in 3 patients, and 1 patient ultimately improved but developed sepsis during the course. Overall, renal outcome was poor in 71% of the cases despite mild chronic renal injury in the biopsy. Conclusion: In adult patients with an HSPlike presentation, a high index of suspicion for underlying Staphylococcal infection is warranted. Blood cultures are frequently negative. Cultures from the site of infection should be performed. Steroid treatment did not improve outcomes. Renal outcomes were frequently poor.
    Clinical nephrology 01/2013; · 1.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) exposes a patient's kidneys to a unique combination of challenges, including high-dose radiation, anemia, chemotherapeutic agents, graft-versus-host disease, opportunistic infections, attenuated and altered immunologic responses, fluid and electrolyte imbalances, and extensive courses of antimicrobial agents. Since the inception of HSCT in the 1950s, there has been increasing interest in defining, determining, and managing the kidney complications that accompany this procedure. In this article, we review the common causes of acute kidney injury and chronic kidney disease that occur with HSCT, including HSCT-associated thrombotic microangiopathy, a distinct cause of chronic kidney disease with a multifactorial cause previously known as bone marrow transplant nephropathy or radiation nephropathy. Additionally, we review other kidney complications, including calcineurin inhibitor nephrotoxicity and chronic graft-versus-host disease-associated glomerulonephritis, that develop post-HSCT. Critically, due to its grave prognosis, it is important to identify HSCT-associated thrombotic microangiopathy early, as well as distinguish it from the other causes of chronic kidney disease.
    American Journal of Kidney Diseases 01/2013; · 5.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is a prototypic, inflammatory autoimmune disease characterized by significant gender bias. Previous studies have established a role for hormones in SLE pathogenesis, including the sex hormone estrogen. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and β into the nucleus where they induce transcription by binding to estrogen response elements (EREs) of target genes. The ZAS3 locus encodes a signaling and transcriptional molecule involved in regulating inflammatory responses. We show that ZAS3 is significantly up-regulated in SLE patients at both the protein and mRNA levels in peripheral blood mononuclear cells (PBMCs). Furthermore, estrogen stimulates the expression of ZAS3 in vitro in several leukocyte and breast cancer cell lines of both human and murine origin. In vivo estrogen treatment mediates induction of tissue specific ZAS3 expression in several lymphoid organs in mice. Estrogen stimulation also significantly up-regulates ZAS3 expression in primary PBMCs, while treatment with testosterone has no effect. Mechanistically, estrogen induces differential ERα binding to putative EREs within the ZAS3 gene and ERα knockdown with siRNA prevents estrogen induced ZAS3 up-regulation. In contrast, siRNA targeting IFNα has no effect. These data demonstrate that ZAS3 expression is directly regulated by estrogen and that ZAS3 is overexpressed in lupus. Since ZAS3 has been shown to regulate inflammatory pathways, its up-regulation by estrogen could play a critical role in female-biased autoimmune disorders.
    Molecular Immunology 11/2012; 54(1):23-31. · 3.00 Impact Factor

Publication Stats

5k Citations
1,031.21 Total Impact Points


  • 1992–2014
    • The Ohio State University
      • • Division of Nephrology
      • • Department of Internal Medicine
      • • Division of General Internal Medicine
      • • Division of Hospital Medicine
      Columbus, Ohio, United States
  • 2011–2013
    • Tuen Mun Hospital
      • Department of Medicine
      Hong Kong, Hong Kong
  • 2010
    • Columbia University
      • Division of Nephrology
      New York City, NY, United States
  • 2009
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States
  • 2005–2007
    • University of California, Los Angeles
      • Division of Rheumatology
      Los Angeles, CA, United States
  • 2003
    • Brigham and Women's Hospital
      • Division of Renal Medicine
      Boston, MA, United States
  • 1990–1991
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
    • Washington University in St. Louis
      • Department of Medicine
      Saint Louis, MO, United States