[Development, clinical manifestations and diagnosis of retinal changes in chronic kidney disease]. / Osobennosti razvitiya, klinicheskie proyavleniya i diagnostika izmenenii setchatki pri khronicheskoi bolezni pochek.

Chronic kidney disease (CKD) is a significant public health problem with a high risk of developing age-dependent eye diseases. Renal glomeruli and the choroid have similar structures and vascular networks; the internal hematoretinal barrier and the glomerular filtration barrier have similar developmental path; the renin-angiotensin-aldosterone hormonal system is found in both the eye and the kidneys. All this determines the similarity of physiological and pathogenetic features of the development of diseases associated with these organs. The article discusses general risk factors and pathophysiological mechanisms of development of retinal and renal lesions in CKD, the influence of various factors of pathogenesis on their development and progression. The anatomical similarity of vascularization, accompanied by microvascular changes in the retina and kidneys, leads to similar complications in both organs. Optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) are accurate, well reproducible and non-invasive methods for diagnosing and assessing changes in the retinal microvascular bed, which make it possible to assess microvasculature changes in the kidneys. In CKD, the retina shows signs of impaired capillary perfusion, a decrease in their density, expansion of intercapillary spaces, a rarefaction of the density of the parafoveolar capillary network, which may indicate a decrease in peritubular capillary blood flow, blood circulation of the kidneys in general and their ischemia. Significant thinning of the retina and choroid, along with a decrease in macular volume, even in the initial stages of CKD, is accompanied by impaired renal function (changes in the estimated glomerular filtration rate and urinary albumin excretion), which is a sign of systemic microvascular lesion and pathological process in the kidneys. Therefore, monitoring of retinal vessels using OCT and OCT-A can become a reliable indicator of the progression of renal microvascular changes at any stage of the disease.

STAT4 contributes to adipose tissue inflammation and atherosclerosis.

Adipose tissue (AT) inflammation is an emerging factor contributing to cardiovascular disease. STAT4 is a transcription factor expressed in adipocytes and in immune cells and contributes to AT inflammation and insulin resistance in obesity. The objective of this study was to determine the effect of STAT4 deficiency on visceral and peri-aortic AT inflammation in a model of atherosclerosis without obesity. Stat4(-/-)Apoe(-/-) mice and Apoe(-/-) controls were kept either on chow or Western diet for 12 weeks. Visceral and peri-aortic AT were collected and analyzed for immune composition by flow cytometry and for cytokine/chemokine expression by real-time PCR. Stat4(-/-)Apoe(-/-) and Apoe(-/-) mice had similar body weight, plasma glucose, and lipids. Western diet significantly increased macrophage, CD4+, CD8+, and NK cells in peri-aortic and visceral fat in Apoe(-/-) mice. In contrast, in Stat4(-/-)Apoe(-/-) mice, a Western diet failed to increase the percentage of immune cells infiltrating the AT. Also, IL12p40, TNFa, CCL5, CXCL10, and CX3CL1 were significantly reduced in the peri-aortic fat in Stat4(-/-)Apoe(-/-) mice. Importantly, Stat4(-/-)Apoe(-/-) mice on a Western diet had significantly reduced plaque burden vs Apoe(-/-) controls. In conclusion, STAT4 deletion reduces inflammation in peri-vascular and visceral AT and this may contribute via direct or indirect effects to reduced atheroma formation.

Interaction between cytokines and inflammatory cells in islet dysfunction, insulin resistance and vascular disease.

Inflammation is an established pathogenic player in insulin resistance, islet demise and atherosclerosis. The complex interactions between cytokines, immune cells and affected tissues result in sustained inflammation in diabetes and atherosclerosis. 12- and 15-lipoxygenase (LO), such as 12/15-LO, produces a variety of metabolites through peroxidation of fatty acids and potentially contributes to the complex molecular crosstalk at the site of inflammation. 12- and 15-LO pathways are frequently activated in tissues affected by diabetes and atherosclerosis including adipose tissue (AT), islets and the vasculature. Moreover, mice with whole body and tissue-specific knockout of 12/15-LO are protected against insulin resistance, hyperglycaemia and atherosclerosis supporting functional contribution of 12- and 15-LO pathways in diabetes and atherosclerosis. Recently, it has emerged that there is a temporal regulation of the particular isoforms of 12- and 15-LO in human AT and islets during the development of type 1 and type 2 diabetes and obesity. Analyses of tissues affected by diabetes and atherosclerosis also implied the roles of interleukin (IL)-12 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1) in islets and IL-17A in atherosclerosis. Future studies should aim to test the efficacy of inhibitions of these mediators for treatment of diabetes and atherosclerosis.

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice.

Adipose tissue inflammation and reduced pancreatic ß-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin (P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction (P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

[The regulation of blood neutrophil functions by C-reactive protein and serum amyloid P]. / Reguliatsiia funktsii neitrofilov krovi C-reaktivnym belkom i syvorotochnym amiloidom P.

The effect of C-reactive protein on oxygen metabolism and lysosomal activity of the human blood neutrophils was found to depend on its ability to conform and to render both the pro- and anti-inflammatory results. The serum amyloid P exerted mostly a consistent anti-inflammatory effect.