Renal artery stenosis: epidemiology and treatment.

Renal artery stenosis (RAS) is a frequently encountered problem in clinical practice. The disease encompasses a broad spectrum of pathophysiologies and is associated with three major clinical syndromes: ischemic nephropathy, hypertension, and destabilizing cardiac syndromes. The two most common etiologies are fibromuscular dysplasia and atherosclerotic renal artery disease with atherosclerotic disease accounting for the vast majority of cases. Atherosclerotic renovascular disease has considerable overlap with atherosclerotic disease elsewhere and is associated with a poor prognosis. A wide range of diagnostic modalities and treatment approaches for RAS are available to clinicians, and with the advent of endovascular interventions, selecting the best course for a given patient has only grown more challenging. Several clinical trials have demonstrated some benefit with revascularization but not to the extent that many had hoped for or expected. Furthermore, much of the existing data is only marginally useful given significant flaws in study design and inherent bias. There remains a need for further identification of subgroups and appropriate indications in hopes of maximizing outcomes and avoiding unnecessary procedures in patients who would not benefit from treatment. In recent decades, the study of RAS has expanded and evolved rapidly. In this review, we will attempt to summarize the amassed body of literature with a focus on the epidemiology of RAS including prevalence, overlap with other atherosclerotic disease, and prognosis. We will also outline existing diagnostic and treatment approaches available to clinicians as well as summarize the findings of several major clinical trials. Finally, we will offer our perspective on future directions in the field.

Mapping of a microbial protein domain involved in binding and activation of the TLR2/TLR1 heterodimer.

The pentameric B subunit of type IIb Escherichia coli enterotoxin (LT-IIb-B(5)), a doughnut-shaped oligomeric protein from enterotoxigenic E. coli, activates the TLR2/TLR1 heterodimer (TLR2/1). We investigated the molecular basis of the LT-IIb-B(5) interaction with TLR2/1 to define the structure-function relationship of LT-IIb-B(5) and, moreover, to gain an insight into how TLR2/1 recognizes large, nonacylated protein ligands that cannot fit within its lipid-binding pockets, as previously shown for the Pam(3)CysSerLys(4) (Pam(3)CSK(4)) lipopeptide. We first identified four critical residues in the upper region of the LT-IIb-B(5) pore. Corresponding point mutants (M69E, A70D, L73E, S74D) were defective in binding TLR2 or TLR1 and could not activate APCs, despite retaining full ganglioside-binding capacity. Point mutations in the TLR2/1 dimer interface, as determined in the crystallographic structure of the TLR2/1-Pam(3)CSK(4) complex, resulted in diminished activation by both Pam(3)CSK(4) and LT-IIb-B(5). Docking analysis of the LT-IIb-B(5) interaction with this apparently predominant activation conformation of TLR2/1 revealed that LT-IIb-B(5) might primarily contact the convex surface of the TLR2 central domain. Although the TLR1/LT-IIb-B(5) interface is relatively smaller, the leucine-rich repeat motifs 9-12 in the central domain of TLR1 were found to be critical for cooperative TLR2-induced cell activation by LT-IIb-B(5). Moreover, the putative LT-IIb-B(5) binding site overlaps partially with that of Pam(3)CSK(4); consistent with this, Pam(3)CSK(4) suppressed TLR2 binding of LT-IIb-B(5), albeit not as potently as self-competitive inhibition. We identified the upper pore region of LT-IIb-B(5) as a TLR2/1 interactive domain, which contacts the heterodimeric receptor at a site that is distinct from, although it overlaps with, that of Pam(3)CSK(4).