Особливості імуно-гормонального та мікробіологічного статусу у жінок з різними морфологічними формами поліпів ендометрія

Обследовано 58 женщин с полипами эндометрия. Выявлены особенности микробиологического пейзажа, гормонального и иммунного статуса в зависимости от морфологических форм полипов эндометрия. проведенный анализ позволил выделить группы риска по развитию полипов эндометрия. показано, что полип эндометрия следует рассматривать не как местный процесс, а как реакцию эндометрия в ответ на повреждение гормонального и иммунного гомеостаза, что необходимо учитывать при выборе лечения данной патологии58 women with endometrial polyps were investigated. Specific microflora and hormonal and immune status depending on the morphological forms of endometrial polyps were found. The analysis performed allowed to allocate risk groups according to development of endometrial polyp. It was shown that endometrial polyp shall be considered as endometrial reaction in response to hormonal and immune homeostasis disorder, rather than local process. This should be borne in mind when choosing treatment for this patholog

In mice, proteinuria and renal inflammatory responses to albumin overload are strain-dependent.

BACKGROUND: The availability of genetically modified mice has increased the need for relevant mouse models of renal disease, but widely used C57BL/6 mice often show resistance to proteinuria. 129/Sv mice are considered more sensitive to certain renal models. Albumin overload, an important model of proteinuric disease, induces marked proteinuria in rats but barely in C57BL/6 mice. We hypothesized that albumin overload would induce more proteinuria in 129S2/Sv than C57BL/6J mice. METHODS: Male and female C57BL/6J and 129S2/Sv mice received bovine serum albumin (BSA) for 11 days. Control groups received saline injections. Injected BSA was immunohistochemically localized to study intrarenal handling of overloaded protein. Renal macrophage infiltration (F4/80 immuno-staining) and glomerular ultrastructure (electron microscopy) were assessed. RESULTS: The BSA-treated groups were similarly hyperproteinemic at Day 11 (D11). Proteinuria differed widely. In C57BL/6J mice, it remained unchanged in females but significantly, though mildly, increased in males (from 3+/-1 to 8+/-2 mg/day, P < 0.05). In 129S2/Sv, proteinuria was marked in both males and females (4+/-1 to 59+/-14, and 0.6+/-0.2 to 29+/-9 mg/day, respectively, both P < 0.01). Proteinuria was accompanied by tubulo-interstitial macrophage infiltration in 129S2/Sv mice. Injected BSA was visualized within glomeruli in both strains and in the urinary space and tubules of 129S2/Sv but not C57BL/6J mice, indicating much greater glomerular leakage in the former. No glomerular macrophages or ultra-structural differences were detected. CONCLUSION: There are major strain differences in the proteinuria and renal inflammatory response of mice to albumin overload, which are not due to structural variation in the filtration barrier but possibly to functional differences in glomerular protein permeability

CCN2 reduction mediates protective effects of BMP7 treatment in obstructive nephropathy

Treatment with rhBMP7 exerts profound protective effects in a wide variety of experimental models of renal disease. However, little is known about how these protective effects are mediated, and which cells in the kidney are targeted by exogenous rhBMP7 treatment. To determine if rhBMP7 increases glomerular and tubulointerstitial canonical BMP signaling, we performed Unilateral Ureteral Obstruction w(UUO, a widely used obstructive nephropathy model) in mice reporting transcriptional activity downstream of canonical BMP signaling by the expression of GFP under the BMP Responsive Element of the Id1 promoter (BRE:gfp mice). We also analysed the impact of rhBMP7 treatment on severity of the UUO phenotype, on TGFβ signaling, and on expression of CCN2 (CTGF). Despite profound protective effects with respect to morphological damage, macrophage infiltration, and fibrosis, no significant difference in GFP-expression was observed upon rhBMP7 administration. Also TGFβ signalling was similar in rhBMP7 and vehicle treated mice, but CCN2 expression in obstructed kidneys was significantly reduced by rhBMP7 treatment. Of note, in heterozygous CCN2 mice (CCN2+/−) treatment with rhBMP7 did not (further) reduce the severity of kidney damage in the UUO-model. These data suggest that protection against obstructive nephropathy by exogenous rhBMP7 treatment relies primarily on non-canonical BMP signaling, and may be mediated in large part by downregulation of CCN2 expression

Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage

Chronickidneydisease (CKD)ischaracterized bypersistent inflammationandprogressive fibrosis,ultimatelyleadingto end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor-α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.This work was supported by the Instituto de Salud Carlos III and Fondos FEDER European Union (PI014/00041, PI17/00119), Red de Investigación Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), and Sociedad Española de Nefrología. The “Juan de la Cierva de Formacion” training program of the Ministerio de Economía, Industria y Competitividad, Gobierno de España supported the salary of SR-M (FJCI-2016-29050)

До мінералогії сезонних сульфатів мису Фіолент (Південно-Західний Крим)

Комплексом методів вивчено колекцію зразків вторинних мінералів одного з узбережних відслонень зони окиснення сульфідної мінералізації мису Фіолент (Південно-Західний Крим). Установлено, що всі досліджені зразки є полімінеральними утвореннями, в яких одночасно співіснують у різних пропорціях сульфати Mg, Al, Fe²⁺, Fe³⁺, Ca тощо: пікерингіт (найпоширеніший), пікерингіт залізистий, гексагідрит, старкіїт, епсоміт, алуноген, ботріоген, копіапіт, ярозит, гіпс та ін. Старкіїт і ботріоген у Криму виявлено вперше.The collection of secondary minerals from one of littoral occurrences of sulphide zone of oxidation of the Fiolent Cape (South-Western Crimea) is studied by different methods. It was established that all studied samples were polymineral formations which consisted of sulphates of Mg, Al, Fe²⁺, Fe³⁺, Ca, etc. in different proportions: pickeringite (the most wide-spread), ferropickeringite, hexahydrite, starkeyite, epsomite, alunogen, botryogen, copiapite, jarosite, gypsum etc. Starkeyite and botryogen are detected in the Crimea for the first time

Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis

CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, fu

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

ephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.United States. National Institutes of Health (R01- CA075576)United States. National Institutes of Health (R01-CA055042)United States. National Institutes of Health (R01-CA149261)United States. National Institutes of Health (AGSS- 3046-12)United States. National Institutes of Health (P30-ES02109)United States. National Institutes of Health (P30-CA014051

Inflammatory and fibrotic mediators in renal diseases

This work was supported by the Instituto de Salud Carlos III and Fondos FEDER European Union (PI014/00041, PI17/00119), Red de Investigación Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), and Sociedad Española de Nefrología. The “Juan de la Cierva de Formacion” training program of the Ministerio de Economía, Industria y Competitividad, Gobierno de España, supported the salary of SR-M (FJCI-2016-2905

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

腎不全治療の新しい可能性の発見－腎不全をきたす遺伝病、アルポート症候群はBMP阻害分子USAG-1欠損によって軽快し、腎不全に陥らない－. 京都大学プレスリリース. 2010-02-09. http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2009/100209_1.htmThe glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization–associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3–/– mice, which model Alport syndrome. Ablation of Usag1 in Col4a3–/– mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span.Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3–/– mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome