The podocyte: glomerular sentinel at the crossroads of innate and adaptive immunity.

Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with the nephrotic syndrome and has a propensity to recur following kidney transplantation. The pathophysiology and therapies available to treat FSGS currently remain elusive. Since the podocyte appears to be the target of apparent circulating factor(s) that lead to recurrence of proteinuria following kidney transplantation, this article is focused on the podocyte.

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice.

Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice.

Novel mechanism for estrogen receptor alpha modulation of murine lupus.

Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERα) knockout (KO) mice are used for defining hormone receptor effects in lupus.

Complete knockout of estrogen receptor alpha is not directly protective in murine lupus.

Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease that disproportionately affects women. Despite a known role for hormonal factors impacting autoimmunity and disease pathogenesis, the specific mechanisms of action remain poorly understood. Our laboratory previously backcrossed "estrogen receptor alpha knockout (ERαKO)" mice onto the NZM2410 lupus prone background to generate NZM/ERαKO mice.

Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse.

Systemic lupus erythematosus (SLE) occurs nine times more often in females than males. The purpose of this study was to determine the impact of estrogen receptor (ER) null genotypes on disease in lupus prone NZM2410 (NZM) and MRL/lpr mice, as a method to define the role of estrogen receptor signaling in lupus. ER alpha deficient NZM females, but not males, had significantly prolonged survival, reduced proteinuria, renal pathology scores and serum urea nitrogen levels compared to wildtype mice, despite higher serum anti-dsDNA levels.

Liver biopsy interpretation for causes of late liver allograft dysfunction.

Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury.

Effects of complement factor D deficiency on the renal disease of MRL/lpr mice.

Background: The alternative complement pathway (AP) is activated in individuals with lupus nephritis and in murine models of systemic lupus erythematosus, including MRL/lpr mice. A previous study from our laboratory evaluated the development of renal disease in MRL/lpr mice genetically deficient in factor B (Bf-/-), a protein necessary for AP activation. MRL/lpr Bf-/- mice developed less renal disease and had improved survival; however, these mice were also a different major histocompatibility complex (MHC) haplotype (H-2b) than their wild-type littermates (H-2k) due to the gene for Bf being located in the MHC gene complex.

Effect of genetic deficiency of terminal deoxynucleotidyl transferase on autoantibody production and renal disease in MRL/lpr mice.

Terminal deoxynucleotidyl transferase (TdT) places non-template-coded nucleotides (N additions) in the VH CDR3 of T cell receptors and immunoglobulins. Amino acids coded for by N additions are important in autoantibody binding of dsDNA in lupus. We hypothesized that a genetic lack of TdT would modulate disease in lupus-prone mice.

Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse.

Studies in human systemic lupus erythematosus (SLE) suggest a possible role for histone deacetylases (HDACs) in skewed gene expression and disease pathogenesis. We used the MRL-lpr/lpr murine model of lupus to demonstrate that HDACs play a key role in the heightened levels of both Th1 and Th2 cytokine expression that contribute to disease. The availability of specific HDAC inhibitors (HDIs) such as trichostatin A (TSA) and suberonylanilide hydroxamic acid (SAHA) permits the study of the role of HDACs in gene regulation.

Modulation of renal disease in MRL/lpr mice by pharmacologic inhibition of inducible nitric oxide synthase.

Background: MRL-MPJFaslpr (MRL/lpr) mice spontaneously develop lupus-like disease characterized by immune complex glomerulonephritis and overproduction of nitric oxide (NO). Blocking NO production pharmacologically by a non-specific nitric oxide synthase (NOS) inhibitor ameliorated renal disease in MRL/lpr mice while genetically deficient inducible NOS (iNOS) mice developed proliferative glomerulonephritis similar to wild-type controls.

Methods: To clarify the role of iNOS in the pathogenesis of nephritis in MRL/lpr mice, we treated mice with two different NOS inhibitors.