The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT1 and AT2) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT1, AT2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases.

• Klíčová slova
• Angiotensin II, Angiotensin-(1-7), Renin-angiotensin system, TG7371 transgenic rat,
• MeSH
• angiotensin I * metabolismus   MeSH
• angiotensin II * MeSH
• kardiovaskulární nemoci metabolismus   genetika   MeSH
• krevní tlak fyziologie   MeSH
• krysa rodu Rattus MeSH
• ledviny metabolismus   MeSH
• nemoci ledvin metabolismus   genetika   MeSH
• peptidové fragmenty * metabolismus   MeSH
• potkani Sprague-Dawley * MeSH
• potkani transgenní * MeSH
• protoonkogen Mas MeSH
• receptor angiotensinu typ 1 genetika   metabolismus   MeSH
• receptory spřažené s G-proteiny genetika   metabolismus   MeSH
• rekombinantní fúzní proteiny metabolismus   MeSH
• renin-angiotensin systém * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• angiotensin I (1-7) MeSH Prohlížeč
• angiotensin I * MeSH
• angiotensin II * MeSH
• peptidové fragmenty * MeSH
• protoonkogen Mas MeSH
• receptor angiotensinu typ 1 MeSH
• receptory spřažené s G-proteiny MeSH
• rekombinantní fúzní proteiny MeSH

The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.

• MeSH
• aktivace komplementu MeSH
• autoimunitní nemoci * MeSH
• glomerulus patologie   MeSH
• komplement metabolismus   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• nemoci ledvin * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• komplement MeSH

Osteopontin (OPN) is a multifaceted matricellular protein, with well-recognized roles in both the physiological and pathological processes in the body. OPN is expressed in the main organs and cell types, in which it induces different biological actions. During physiological conditioning, OPN acts as both an intracellular protein and soluble excreted cytokine, regulating tissue remodeling and immune-infiltrate in adipose tissue the heart and the kidney. In contrast, the increased expression of OPN has been correlated with the severity of the cardiovascular and renal outcomes associated with obesity. Indeed, OPN expression is at the "cross roads" of visceral fat extension, cardiovascular diseases (CVDs) and renal disorders, in which OPN orchestrates the molecular interactions, leading to chronic low-grade inflammation. The common factor associated with OPN overexpression in adipose, cardiac and renal tissues seems attributable to the concomitant increase in visceral fat size and the increase in infiltrated OPN+ macrophages. This review underlines the current knowledge on the molecular interactions between obesity and the cardiac-renal disorders ruled by OPN.

• Klíčová slova
• cardiovascular diseases (CVDs), chronic kidney disease (CKD), obesity, osteopontin (OPN), renal disorders, visceral adipose tissue (VAT),
• MeSH
• inzulinová rezistence genetika   MeSH
• ledviny metabolismus   patologie   MeSH
• lidé MeSH
• myokard metabolismus   patologie   MeSH
• nemoci ledvin genetika   metabolismus   patologie   MeSH
• nemoci srdce genetika   metabolismus   patologie   MeSH
• nitrobřišní tuk metabolismus   MeSH
• obezita genetika   metabolismus   patologie   MeSH
• osteopontin genetika   metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• zánět genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• osteopontin MeSH

Nephrotoxicity of cisplatin (CP) involves renal oxidative stress and inflammation, and sesamin (a major liganin in many plants) has strong antioxidant and antiinflammatory actions. Therefore, we investigated here the possible mitigative action of sesamin on CP nephrotoxicity in rats. Sesamin was given orally (5 mg/kg/day, 10 days), and on the 7th day, some of the treated rats were injected intraperitoneally with either saline or CP (5 mg/kg). On the 11th day, rats were sacrificed, and blood and urine samples and kidneys were collected for biochemical estimation of several traditional and novel indices of renal damage in plasma and urine, several oxidative and nitrosative indices in kidneys, and assessment of histopathological renal damage. CP significantly and adversely altered all the physiological, biochemical and histopathological indices of renal function measured. Kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with sesamin. Sesamin treatment did not significantly alter the renal CP concentration. The results suggested that sesamin had ameliorated CP nephrotoxicity in rats by reversing the CP-induced oxidative stress and inflammation. Pending further pharmacological and toxicological studies sesamin may be considered a potentially useful nephroprotective agent.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• antitumorózní látky škodlivé účinky   MeSH
• cisplatina škodlivé účinky   MeSH
• dioxoly farmakologie   terapeutické užití   MeSH
• fytoterapie * MeSH
• ledviny účinky léků   metabolismus   MeSH
• lignany farmakologie   terapeutické užití   MeSH
• nemoci ledvin chemicky indukované   farmakoterapie   metabolismus   MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• rostlinné extrakty terapeutické užití   MeSH
• Sesamum * MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• antitumorózní látky MeSH
• cisplatina MeSH
• dioxoly MeSH
• lignany MeSH
• rostlinné extrakty MeSH
• sesamin MeSH Prohlížeč

Long-term peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane. Inflammation may be the key moment, and, consequently, fibrosis may be the end result of chronic inflammatory reaction. The objective of the present study was to identify genes involved in peritoneal alterations during PD by comparing the transcriptome of peritoneal cells in patients with short- and long-term PD. Peritoneal effluent of the long dwell of patients with stable PD was centrifuged to obtain peritoneal cells. The gene expression profiles of peritoneal cells using microarray between patients with short- and long-term PD were compared. Based on microarray analysis, 31 genes for quantitative RT-PCR validation were chosen. A 4-h peritoneal equilibration test was performed on the day after the long dwell. Transport parameters and protein appearance rates were assessed. Genes involved in the immune system process, immune response, cell activation, and leukocyte and lymphocyte activation were found to be substantially upregulated in the long-term group. Quantitative RT-PCR validation showed higher expression of CD24, lymphocyte antigen 9 (LY9), TNF factor receptor superfamily member 4 (TNFRSF4), Ig associated-α (CD79A), chemokine (C-C motif) receptor 7 (CCR7), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and IL-2 receptor-α (IL2RA) in patients with long-term PD, with CD24 having the best discrimination ability between short- and long-term treatment. A relationship between CD24 expression and genes for collagen and matrix formation was shown. Activation of CD24 provoked by pseudohypoxia due to extremely high glucose concentrations in dialysis solutions might play the key role in the development of peritoneal membrane alterations.

• Klíčová slova
• gene expression, peritoneal dialysis, peritoneal membrane alterations,
• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci ledvin genetika   metabolismus   terapie   MeSH
• peritoneální dialýza * MeSH
• peritoneum metabolismus   MeSH
• průřezové studie MeSH
• regulace genové exprese MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkriptom * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

• Klíčová slova
• C3 glomerulonephritis, C3 glomerulopathy, C3 nephritic factor, C4 nephritic factor, Dense deposit disease, Membranoproliferative glomerulonephritis,
• MeSH
• autoprotilátky imunologie   metabolismus   MeSH
• dospělí MeSH
• komplement C3 nefritický faktor metabolismus   MeSH
• komplement metabolismus   MeSH
• lidé MeSH
• membranoproliferativní glomerulonefritida imunologie   metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci ledvin imunologie   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoprotilátky MeSH
• complement 4 nephritic factor MeSH Prohlížeč
• komplement C3 nefritický faktor MeSH
• komplement MeSH

BACKGROUND: Cyclosporine A (CsA) is widely used for organ transplantation and autoimmune disorders. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. The metabolism of CsA has a close relationship with this disease in renal-transplant patients. However, the metabolic pathways of CsA and its metabolizing enzymes have rarely been comprehensively reviewed. In this review, we have summarized the specific metabolic profiles of CsA in humans, especially renal-transplant patients. Moreover, the specific metabolizing enzymes and the potential roles that CsA metabolism plays in CsA nephrotoxicity were summarized and discussed. METHODS: Electronic databases including PubMed, Web of Science, and Scifinder were searched with the keywords "Cyclosporine A and metabolism", and "Cyclosporine A and nephrotoxicity", "Cyclosporine A metabolism and nephrotoxicity". All these studies published until 2018 were included in this review. RESULTS: The major metabolic pathways of CsA in humans are hydroxylation and N-demethylation. Normally, these metabolites are relatively less toxic than CsA. However, the metabolism of CsA in the kidneys is much weaker than that in the liver, which explains why CsA is so toxic to the kidneys. CYP3A families, especially CYP3A4 and CYP3A5, play an important role in the biotransformation of CsA. Moreover, increased lines of evidence show that some metabolites (including AM19) associate directly with nephrotoxicity in CsA-treated organ-transplant patients. CONCLUSION: The findings of this review help to further understand the metabolic activities of CsA in renal-transplant patients and cast some light on the mechanisms of CsA nephrotoxicity.

• Klíčová slova
• Cyclosporine A, metabolic pathways, metabolism, metabolizing enzymes, nephrotoxicity, renal-transplant patients.,
• MeSH
• cyklosporin škodlivé účinky   farmakokinetika   MeSH
• glukosa metabolismus   MeSH
• imunosupresiva škodlivé účinky   farmakokinetika   MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• nemoci ledvin chemicky indukované   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cyklosporin MeSH
• glukosa MeSH
• imunosupresiva MeSH
• systém (enzymů) cytochromů P-450 MeSH

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

• Klíčová slova
• COP vesicles, ER stress, Golgi apparatus, cargo receptor, endoplasmic reticulum, epithelial cells, kidney, organoids, secretory pathway, unfolded protein response,
• MeSH
• benzamidy chemie   metabolismus   farmakologie   MeSH
• epitelové buňky cytologie   metabolismus   MeSH
• heptany farmakologie   terapeutické užití   MeSH
• imidazolinové receptory antagonisté a inhibitory   genetika   metabolismus   MeSH
• indukované pluripotentní kmenové buňky cytologie   metabolismus   MeSH
• ledviny cytologie   metabolismus   patologie   MeSH
• lidé MeSH
• lyzozomy účinky léků   metabolismus   MeSH
• malá interferující RNA metabolismus   MeSH
• mucin 1 chemie   genetika   metabolismus   MeSH
• můstkové bicyklické sloučeniny farmakologie   terapeutické užití   MeSH
• myši transgenní MeSH
• myši MeSH
• nemoci ledvin metabolismus   patologie   MeSH
• posunová mutace MeSH
• RNA interference MeSH
• signální dráha UPR účinky léků   MeSH
• transkripční faktor ATF6 metabolismus   MeSH
• vezikulární transportní proteiny chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATF6 protein, human MeSH Prohlížeč
• benzamidy MeSH
• BRD4780 MeSH Prohlížeč
• heptany MeSH
• imidazolinové receptory MeSH
• malá interferující RNA MeSH
• mucin 1 MeSH
• můstkové bicyklické sloučeniny MeSH
• NISCH protein, human MeSH Prohlížeč
• TMED9 protein, human MeSH Prohlížeč
• transkripční faktor ATF6 MeSH
• vezikulární transportní proteiny MeSH

Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals' whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales-hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.

• Klíčová slova
• amifostine, bone marrow, doxorubicin, hepatotoxicity, nephrotoxicity, rats,
• MeSH
• amifostin farmakologie   MeSH
• doxorubicin škodlivé účinky   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lékové postižení jater metabolismus   patologie   prevence a kontrola   MeSH
• nemoci ledvin chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• orgánová specificita účinky léků   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amifostin MeSH
• doxorubicin MeSH

We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression.

• MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• endotelin-1 biosyntéza   MeSH
• fibróza MeSH
• ischemie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   MeSH
• myši MeSH
• nemoci ledvin farmakoterapie   metabolismus   MeSH
• receptor endotelinu B biosyntéza   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• synthasa oxidu dusnatého, typ III biosyntéza   MeSH
• upregulace účinky léků   fyziologie   MeSH
• vitamin D farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endotelin-1 MeSH
• messenger RNA MeSH
• Nos3 protein, mouse MeSH Prohlížeč
• receptor endotelinu B MeSH
• synthasa oxidu dusnatého, typ III MeSH
• vitamin D MeSH