A gyűjtőcsatorna meghatározó szerepe a vese lokális renin-angiotenzin rendszerében

A renin-angiotenzin rendszer szervezetünk egyik legjelentősebb hormonális rendszere, amelynek juxtaglomerularis apparátusban történő szabályozása és szerepe jól ismert. Jelen összefoglaló a vese embrionális fejlődésével párhuzamot állítva a gyűjtőcsatorna renintermelését írja le, valamint ennek lokális szerepét és terápiás célpontként szolgáló lehetőségeit igyekszik feltárni. Nemrégiben került leírásra, hogy krónikus angiotenzin- II-kezelés során, két vese-, egy klip modellben, illetve diabetes mellitusban a gyűjtőcsatorna jelenti az intrarenalis (pro)renintermelés legfőbb helyét. Ebben a lokalizációban a (pro)renin előtt út nyílhat az interstitialis renin-angoitenzin rendszer komponensek, a szisztémás keringés és a nemrégiben leírásra került (pro)reninreceptor felé. A (pro)renin saját receptorán keresztül intracelluláris profibroticus utakat képes aktiválni, így egyúttal potenciálisan új célpontja lehet a hypertoniához kapcsolódó vagy diabeteses nephropathia kezelésének, illetve eszköze a krónikus vesekárosodást előidéző folyamatok korai diagnosztizálásának. Orv. Hetil., 2013, 154, 643–649

Indeks tjelesne mase, relativna tjelesna mast i rezultati motoričkih testova mađarskih romskih dječaka

The aim of the present comparison of Roma and non-Roma prepubertal boys was to analyse if there were differences in some anthropometric measures and in running performance to see if Roma children fall behind their non-Roma peers in growth and development, and if so, to what extent. Until now no larger child sample of exclusively Roma ethnicity has been investigated concerning their basic somatic and motor performance attributes. Kinanthropometric data collection was carried out in 1,149 volunteer Roma boys aged between 7 and 14. For a control group exactly the same number of non-Roma subjects was selected randomly from each age group of the same region. Height, body mass, BMI, relative body fat content and the time scores in 30m dash and 1,200m run were compared. The Roma children were found to be significantly shorter and lighter than their non-Roma peers. There were no consistent differences between the BMI means, but rela-tive body fat content was consistently greater in the Roma sample. The running performances were better in the non-Roma boys. The greater relative fat content and also the poorer running scores of the Roma chil-dren were attributed to a more hypoactive lifestyle and qualitative and quantitative dietary faults. Since the proportion of GDP that might be used for governmental welfare protection keeps being limited, their nec-essary integration is getting increasingly difficult. Instead of an educational, social and economic catch-up process further issues of segregation can be predicted.Uvod Nekadašnji tradicionalni, ali i današnji, način života, kao i druge kulturološke karakteristike romske etničke skupine (nesklonost integriranju, niska razina obrazovanosti zbog neuključivanja u obrazovni sustav, upadljivo niži opći društveno-ekonomski uvjeti te, posljedično, viša stopa kriminala, zlouporabe droga i alkohola) rezultirali su njihovom manje ili više izraženom segregacijom od ne-romske populacije. Povrh dokazanih etničkih i genetskih čimbenika, ovi okolišni učinci također mogu utjecati na rast i tjelesni razvoj. Stoga je cilj ove usporedbe romskih i ne-romskih dječaka pretpubertetske dobi bio analizirati ima li razlika u nekim antropometrijskim obilježjima i u rezultatima u trčanju da bi se utvrdilo postoji li kod romske djece zaostajanje u rastu i razvoju te, ako postoji, do koje je mjere izraženo. Do sada se još nisu ispitivale osnovne somatske značajke ni karakteristike motoričkog statusa većih uzoraka djece isključivo romske etničke skupine. Metode Prikupljanje kinantropometrijskih podataka provedeno je na uzorku od 1.149 dobrovoljnih ispitanika, romskih dječaka u dobi između 7 i 14 godina. Za kontrolnu skupinu je metodom slučajnog odabira izabran potpuno jednak broj ne-romskih ispitanika za svaku dobnu skupinu. Ispitanici kontrolne skupine odabrani su iz većeg uzorka dječaka koji žive na istom području, a mjerenja su provedena istovremeno u obje skupine. Uspoređene su visina, tjelesna masa, indeks tjelesne mase, relativna količina tjelesne masti i rezultati (vremena) u sprintu na 30m i trčanju na 1200m. Rezultati Utvrđeno je da su romska djeca značajno niža i manje mase od njihovih ne-romskih vršnjaka. Nije bilo dosljednih razlika između srednjih vrijednosti indeksa tjelesne mase, dok je relativna količina tjelesne masti bila dosljedno veća u uzorku romskih dječaka. Ne-romski dječaci su postigli bolje rezultate u trčanju. Veća relativna količina tjelesne masti i slabiji rezultati u trčanju utvrđeni kod romske djece pripisani su manje aktivnom načinu života te kvalitativnim i kvantitativnim nedostacima u prehrani (relativna malnutricija). Rasprava i zaključak Što se tiče uspoređenih karakteristika, dosljedna se razlika između odgovarajućih srednjih vrijednosti visine može povezati s očitom antropološkom (rasnom) razlikom. Neovisno o sjevernoindijskom podrijetlu mađarske populacije Roma (Czeizel, 2003), kao i o njihovom današnjem svakako niskom društveno-ekonomskom statusu (u usporedbi s ne-romskom populacijom Mađarske), srednje vrijednosti visine mađarskih romskih dječaka bile su 1,5-2,0 cm više u svakoj dobnoj skupini u odnosu na romske dječake koji žive u području Patiala, Sjeverna Indija (Singh et al., 1992). Indeksi tjelesne mase ili srednje vrijednosti tjelesne mase u odnosu na visinu indijskih dječaka bili su također manjih vrijednosti. Indeks tjelesne mase, relativna količina tjelesne masti, kao i rezultati u trčanju podjednako su izloženi pritisku načina života. Osobito želimo naglasiti da su sastav tijela i tjelesna motorička sposobnost ne-romskog dijela uzorka (kontrolna skupina) također pod utjecajem današnjeg hipoaktivnog načina života. Utvrđeno je da je srednja vrijednost relativne tjelesne masti značajno porasla u odnosu na vrijednosti od prije 25-30 godina, kada su i rezultati testiranja motoričkih sposobnosti ne-romske djece i adolescenata bili izrazito bolji (Szabó, 1977; Més-záros et al., 1986; Eiben et al., 1991). Napominjemo da se promatrane kinantropometrijske karakteristike ovih romskih dječaka sa sela ne razlikuju značajno od dječaka koji žive u glavnom gradu (Tatár et al., 2003). S obzirom na to, opažene značajne razlike među skupinama mogu se generalizirati. Još je jedna točka ove usporedbe pod mogućim utjecajem vrlo niskih društveno-ekonomskih uvjeta. Mészáros i suradnici (2006) su longitudinalnim istraživanjem dokazali da su srednja vrijednost visine i stopa porasta visine bili manji u velikom uzorku ne-romske djece niskog društveno-ekonomskog statusa. Njihova manja visina je također bila povezana s većim indeksom tjelesne mase i relativnom količinom tjelesne masti, kao i značajno slabijom kardiorespiratornom izdržljivošću. Kako su u na-šoj usporedbi opažene razlike bile još i veće, sličan slijed razmišljanja doveo nas je do pretpostavke o zajedničkim učincima relativne malnutricije (velika razina potrošnje ugljikohidrata i masti, povezana s niskim unosom esencijalnih proteina, vitamina i minerala) i izrazito hipoaktivnog načina života. Prema tim opažanjima, čimbenik malnutricije ne može se izostaviti kod interpretiranja značajno manje visine romskih dječaka. Promatraju li se samo dobiveni podaci, ne mogu se jasno razabrati moguća objašnjenja opaženih razlika. Želimo naglasiti da sadašnja generacija romske djece nema prave šanse izrasti u odrasle osobe koje bi bile zdravije no što su to njihovi roditelji danas. S obzirom na to da je a) natalitet u romskim obiteljima znatno veći nego u ne-romskim (Babusik 2002), udio romske etničke skupine je u stalnom porastu – prema predviđanjima (Kertesi i Kézdi 1998), taj će udio do 2010. godine iznositi više od 10% te da je b) postotak bruto društvenog proizvoda koji vlada može koristiti za socijalnu skrb i zaštitu ograničen, nužna integracija romske etničke skupine postaje sve teža. Umjesto procesa smanjivanja razlika između romske i ne-romske populacije na obrazovnom, društvenom i ekonomskom planu, mogu se predvidjeti daljnji segregacijski problemi

Heat Shock Protein Polymorphism Predisposes to Urinary Tract Malformations and Renal Transplantation in Children

Background. Anatomical malformations of the kidney and urinary tract account for 17% of pediatric renal transplantation procedures. Heat shock proteins (HSPs) are molecular chaperones with a protective function that promotes cell survival. HSP72 is an endogenous ligand for toll-like receptor TLR4, thereby stimulating innate immunity. Both in adults and children, decreased expression of HSP70s is associated with a number of kidney diseases. Objective. To assess the prevalence of HSPA1A G(190)C, HSPA1B A(1267)G, and TLR4 A(896)G polymorphisms in children who had undergone kidney transplantation. Patients and Methods. Genotypes were analyzed using allele-specific polymerase chain reaction in 41 pediatric recipients. Allelic prevalence was related to reference values in 65 age- and sex- matched healthy children. Results. Clinical data did not reveal a difference between any of the groups. HSPA1B (1267)GG genotype and HSPA1B (1267)G allele were observed more frequently in the transplant recipients compared with the control group: AA vs AG: odds ratio [OR], 12.6; 95% confidence interval [CI], 1.58-100.0; P = .004; AA vs GG: OR, 20.80; 95% CI, 2.32-187.00; P = .01; and A vs G: OR, 2.10; 95% CI, 1.19-3.07; P = .01. Furthermore, the prevalence of the HSPAIB (1267)GG genotype was greater in transplant recipients with vs without urinary tract malformations: AG vs GG: OR, 0.10; 95% CI, 0.09-0.48; P = .007. No differences were observed in the other studied polymorphisms. Conclusion. Our findings suggest an association between the carrier status of HSPA1B (1267)G with urinary tract malformations, leading to end-stage renal disease requiring kidney transplantation. This observation raises further questions about the clinical and therapeutic relevance of this polymorphism to pediatric nephrology

Increased expression of hypoxia-inducible factor 1alfa in celiac disease

Previously, it has been suggested that hypoxia-inducible factor (HIF) 1 signaling may play determinative role in the maintenance of the barrier function of the intestinal epithelium in inflammatory bowel disease. Our aim was to depict the alteration of HIF-1α and related genes in celiac disease (CD) where the importance of the barrier function is well known. Duodenal biopsy specimens were collected from 16 children with untreated CD, 9 children with treated CD and 10 controls. HIF-1α, trefoil factor 1 (TFF1), ecto-5-prime nucleotidase (CD73), and multi drug resistance gene 1 (MDR1) mRNA and HIF-1α protein expression were determined by real-time PCR and Western blot, respectively. Localization of HIF-1α was determined by immunofluorescent staining. We found increased HIF-1α and TFF1 mRNA and HIF-1α protein expression in the duodenal mucosa of children with untreated CD compared with controls or children with treated CD (p < 0.05). In untreated CD children, HIF-1α staining was present in cytoplasmic and nuclear region of the villous enterocytes. In treated CD mRNA expression of CD73 and MDR1 were increased compared with controls (p < 0.01 and 0.05, respectively). Our results of increased mucosal HIF-1α expression in CD children suggest the contribution of this signaling pathway in the pathomechanism of CD. Copyright © 2010 International Pediatric Research Foundation, Inc

Increased heat shock protein 72 expression in celiac disease

BACKGROUND AND OBJECTIVES: Heat shock protein (HSP) 72, a known chaperone, has potential epithelial barrier protecting, antiapoptotic, and immune system regulatory effects; therefore, our aim was to study its involvement in the pathology of celiac disease (CD). PATIENTS AND METHODS: Duodenal biopsy specimens were collected from children with untreated and treated CD and from controls. mRNA expression, protein level, and localization of HSP72 were determined. RESULTS: Elevated HSP72 mRNA expression and higher protein levels were found in the duodenal mucosa of children with untreated CD as well as in children with treated CD compared with those in controls. In the duodenal mucosa of children with treated CD, HSP72 mRNA expression was decreased and HSP72 protein levels were lower than those in children with untreated CD. We detected intensive HSP72 staining in the villous enterocytes and immune cells of the lamina propria in the duodenal villi of children with untreated CD compared with that in controls. CONCLUSIONS: The increased expression and altered localization of HSP72 in CD indicate that HSP72 should have a role in protection against gliadin-induced cytotoxicity. HSP72 may exert antiapoptotic effect and contribute to preservation of intestinal epithelial barrier integrity. Moreover, HSP72 as a ligand of TLR2 and TLR4 may promote innate immune responses and warn the cells of the potential injury

Visualization of Calcium Dynamics in Kidney Proximal Tubules

Intrarenal changes in cytoplasmic calcium levels have a key role in determining pathologic and pharmacologic responses in major kidney diseases. However, cell-specific delivery of calcium-sensitive probes in vivo remains problematic. We generated a transgenic rat stably expressing the green fluorescent protein-calmodulin-based genetically encoded calcium indicator (GCaMP2) predominantly in the kidney proximal tubules. The transposon-based method used allowed the generation of homozygous transgenic rats containing one copy of the transgene per allele with a defined insertion pattern, without genetic or phenotypic alterations. We applied in vitro confocal and in vivo two-photon microscopy to examine basal calcium levels and ligand- and drug-induced alterations in these levels in proximal tubular epithelial cells. Notably, renal ischemia induced a transient increase in cellular calcium, and reperfusion resulted in a secondary calcium load, which was significantly decreased by systemic administration of specific blockers of the angiotensin receptor and the Na-Ca exchanger. The parallel examination of in vivo cellular calcium dynamics and renal circulation by fluorescent probes opens new possibilities for physiologic and pharmacologic investigations

Calcineurin-Inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts.

BACKGROUND: Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD). METHODS: Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining. RESULTS: The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands. CONCLUSIONS: Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity