Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

Combined effect of hyperfiltration and renin angiotensin system activation on development of chronic kidney disease in diabetic db/db mice.

BACKGROUND: Hypertension is a major risk factor for renal disease progression. However, the mechanisms by which hypertension aggravates the effects of diabetes on the kidney are incompletely understood. We tested the hypothesis that renovascular hypertension accelerates angiotensin-II-dependent kidney damage and inflammation in the db/db mouse, a model of type II diabetes. METHODS: Renovascular hypertension was established in db/db and wild-type control mice through unilateral renal artery stenosis (RAS); the non-stenotic contralateral kidneys evaluated 2, 4 and 6 weeks later. Angiotensin-II infusion (1000 ng/kg/min), unilateral nephrectomy, or both were also performed in db/db mice to discern the contributions of hypertension versus hyperfiltration to development of chronic renal injury in db/db mice with RAS. The effect of blood pressure reduction in db/db mice with RAS was assessed using angiotensin-receptor-blocker (ARB) or hydralazine treatment. RESULTS: Db/db mice with renovascular hypertension developed greater and more prolonged elevation of renin activity than all other groups studied. Stenotic kidneys of db/db mice developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Contralateral kidneys of wild type mice with RAS showed minimal histopathologic abnormalities, whereas db/db mice with RAS developed severe diffuse mesangial sclerosis, interstitial fibrosis, tubular atrophy, and interstitial inflammation. Db/db mice with Angiotensin II-induced hypertension developed interstitial lesions and albuminuria but not mesangial matrix expansion, while nephrectomized db/db mice exhibited modest mesangial expansion and interstitial fibrosis, but not significant albuminuria. The combination of unilateral nephrectomy and angiotensin II infusion reproduced all the features of the injury albeit in a less severe manner. ARB and hydralazine were equally effective in attenuating the development of mesangial expansion in the contralateral kidneys of db/db mice with RAS. However, only ARB prevented elevation of urinary albumin/creatinine in db/db mice with RAS. CONCLUSION: Renovascular hypertension superimposed on diabetes exacerbates development of chronic renal disease in db/db mice at least in part through interaction with the renin-angiotensin system. Both ARB and hydralazine were equally effective in reducing systolic blood pressure and in preventing renal injury in the contralateral kidney of db/db mice with renal artery stenosis. ARB but not hydralazine prevented elevation of urinary albumin/creatinine in the db/db RAS model.

Interventions for anxiety and depression in patients with atopic dermatitis: a systematic review and meta-analysis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with anxiety and depression. Few studies have addressed interventions for symptoms of anxiety and depression in this population. To determine the efficacy of interventions for anxiety and depression in patients with AD. PubMed, MEDLINE, EMBASE, and PsycINFO were searched from inception to November 2023. English-language studies published in peer-reviewed journals evaluating the effect of interventions on anxiety and/or depression using validated assessment tools on patients with AD were included. Titles, abstracts, and articles were screened by at least two independent reviewers. Of 1410 references that resulted in the initial search, 17 studies were included. Fourteen of these studies are randomized controlled trials, while the other 3 studies are prospective controlled trials with pre and post-test designs. Data were extracted using a standardized extraction form, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. To accommodate trials with multiple interventions (each compared to a control group), we conducted a mixed-effects meta-analysis with the trial as a random effect. Prespecified outcomes were changes in symptoms of anxiety and depression in patients with AD as evaluated using standardized assessment tools. Of the 17 studies included in this systematic review, 7 pharmacological intervention studies with 4723 participants examining 5 different medications were included in a meta-analysis. Of these studies, only 1 study evaluated medications prescribed to treat anxiety and/or depression; the rest evaluated medications prescribed to treat AD. Meta-analysis of all the pharmacological interventions resulted in significant improvement in anxiety, depression, and combined anxiety-depression scale scores (standardized mean difference [95% CI]: - 0.29 [- 0.49 to - 0.09], - 0.27 [- 0.45 to - 0.08], - 0.27 [- 0.45 to - 0.08]) respectively. The 10 non-pharmacological studies with 2058 participants showed general improvement in anxiety but not depression. A meta-analysis of the non-pharmacological interventions was not conducted due to variable approaches and limited data. Pharmacological interventions designed to improve AD were found to improve anxiety and depression in patients with moderate-severe disease. More comprehensive studies on non-pharmacological and pharmacological interventions that primarily target anxiety and depression are needed.

Redox signaling is an early event in the pathogenesis of renovascular hypertension.

Activation of the renin-angiotensin-aldosterone system plays a critical role in the development of chronic renal damage in patients with renovascular hypertension. Although angiotensin II (Ang II) promotes oxidative stress, inflammation, and fibrosis, it is not known how these pathways intersect to produce chronic renal damage. We tested the hypothesis that renal parenchymal cells are subjected to oxidant stress early in the development of RVH and produce signals that promote influx of inflammatory cells, which may then propagate chronic renal injury. We established a reproducible murine model of RVH by placing a tetrafluoroethylene cuff on the right renal artery. Three days after cuff placement, renal tissue demonstrates no histologic abnormalities despite up regulation of both pro- and anti-oxidant genes. Mild renal atrophy was observed after seven days and was associated with induction of Tnfα and influx of CD3⁺ T cells and F4/80⁺ macrophages. By 28 days, kidneys developed severe renal atrophy with interstitial inflammation and fibrosis, despite normalization of plasma renin activity. Based on these considerations, we propose that renal parenchymal cells initiate a progressive cascade of events leading to oxidative stress, interstitial inflammation, renal fibrosis, and atrophy.

Vascular Endothelial Growth Factor as an Immediate-Early Activator of Ultraviolet-Induced Skin Injury.

The negative health consequences of acute ultraviolet (UV) exposure are evident, with reports of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. The acute effects of sunburn include erythema, edema, severe pain, and chronic overexposure to UV radiation, leading to skin cancer. Whereas the pain associated with the acute effects of sunburn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative and long-term pathological effects of UV exposure, an unmet clinical need. Here we show that activation of the vascular endothelial growth factor (VEGF) pathway is a direct and immediate consequence of acute UV exposure, and activation of VEGF signaling is necessary for initiating the acute pathological effects of sunburn. In UV-exposed human subjects, VEGF signaling is activated within hours. Topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small-molecule antagonists of VEGF receptor signaling, prevent the development of erythema and edema in UV-exposed mice. These findings collectively suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, revealing a new postexposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin. It is essential to emphasize that these preclinical studies must not be construed as suggesting in any way the use of VEGF inhibitors as a sunburn treatment in humans because warranted future clinical studies and appropriate agency approval are essential in that regard.

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.

White dot syndromes: a 20-year study of incidence, clinical features, and outcomes.

PURPOSE: To measure the incidence of white dot syndromes (WDS) in a community-based population and to report clinical features and outcomes. METHODS: Multicenter retrospective study using the Rochester Epidemiology Project medical records linkage system of Olmsted County, Minnesota. Databases were searched to identify all patients with WDS from January 1, 1988 through December 31, 2008. RESULTS: Mean ophthalmic follow-up was 4.5 years and mean general medical follow-up was 9.1 years. The incidence of WDS was 0.45 per 100,000 per year (95% CI 0.19-0.71). Incidence rates for specific disease entities were also calculated. The authors report some associated autoimmune diseases in this series. Multiple evanescent white dot syndrome (MEWDS) was more common in females, and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was more common in males. Both MEWDS and APMPPE generally carried a good visual prognosis. Fifty percent of cases with APMPPE had a positive history of psoriasis. The only punctuate inner choroidopathy (PIC) case carried that diagnosis as well. CONCLUSIONS: WDS are rare diseases and may be associated with other autoimmune diseases. Further studies with more patients and longer follow-up periods are needed to draw conclusions about visual prognosis, development of other ocular conditions, and associated medical diseases.