Article

Activated intrarenal reactive oxygen species and renin angiotensin system in IgA nephropathy

Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
Minerva urologica e nefrologica = The Italian journal of urology and nephrology (Impact Factor: 0.7). 04/2009; 61(1):55-66.
Source: PubMed

ABSTRACT Immunoglobulin A (IgA) nephropathy is recognized worldwide as the most common primary glomerulopathy. Although the mechanisms underlying the development of IgA nephropathy are gradually being clarified, their details remain unclear, and a radical cure for this condition has not yet been established. It has been clinically demonstrated that the immunoreactivities of intrarenal heme oxygenase-1 (HO-1) and 4-hydroxy-2-nonenal (4-HNE) markers of reactive oxygen species (ROS) and those of intrarenal angiotensinogen (AGT) and angiotensin II (Ang II) markers of renin angiotensin system (RAS) in IgA nephropathy patients were significantly increased as compared to those of control subjects. In an animal study, high IgA of ddY (HIGA) mice were used as an IgA nephropathy model and compared with BALB/c mice, which served as the control. The levels of markers for ROS (urinary 8-isoprostane and intrarenal 4-HNE), RAS (intrarenal AGT and Ang II), and renal damage in the HIGA mice were significantly increased as compared to those in the BALB/c mice. Moreover, an interventional study using HIGA mice demonstrated that the expressions of 2 lines of intrarenal ROS markers (4-HNE and HO-1), 2 lines of intrarenal RAS markers (AGT and Ang II) and renal damage decreased significantly in HIGA mice receiving treatment with the Ang II receptor blocker olmesartan but not in HIGA mice receiving treatment with RAS-independent antihypertensive drugs (hydralazine, reserpine, and hydrochlorothiazide) when compared with HIGA mice that were not treated. These data suggest that intrarenal ROS and RAS activation plays a pivotal role in the development of IgA nephropathy.

0 Followers
 · 
88 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal recessive disease, enriched in the Finnish population. NPHS1 is caused by a mutation in the NPHS1 gene. This gene encodes for nephrin, which is a major structural component of the slit diaphragm connecting podocyte foot processes in the glomerular capillary wall. In NPHS1, the genetic defect in nephrin leads to heavy proteinuria already in the newborn period. Finnish NPHS1 patients are nephrectomized at infancy, and after a short period of dialysis the patients receive a kidney transplant, which is the only curative therapy for the disease. In this thesis, we examined the cellular and molecular mechanisms leading to the progression of glomerulosclerosis and tubulointerstitial fibrosis in NPHS1 kidneys. Progressive mesangial expansion in NPHS1 kidneys is caused by mesangial cell hyperplasia and the accumulation of extracellular matrix proteins. Expansion of the extracellular matrix was caused by the normal mesangial cell component, collagen IV. However, no significant changes in mesangial cell phenotype or extracellular matrix component composition were observed. Endotheliosis was the main ultrastructural lesion observed in the endothelium of NPHS1 glomeruli. The abundant expression of vascular endothelial growth factor and its transcription factor hypoxia inducible factor-1 alpha were in accordance with the preserved structure of the endothelium in NPHS1 kidneys. Hypoperfusion of peritubular capillaries and tubulointerstitial hypoxia were evident in NPHS1 kidneys, indicating that these may play an important role in the rapid progression of fibrosis in the kidneys of NPHS1 patients. Upregulation of Angiotensin II was obvious, emphasizing its role in the pathophysiology of NPHS1. Excessive oxidative stress was evident in NPHS1 kidneys, manifested as an increase expression of p22phox, superoxide production, lipid oxide peroxidation and reduced antioxidant activity. In conclusion, our data indicate that mesangial cell proliferation and the accumulation of extracellular matrix accumulation are associated with the obliteration of glomerular capillaries, causing the reduction of circulation in peritubular capillaries. The injury and rarefaction of peritubular capillaries result in impairment of oxygen and nutrient delivery to the tubuli and interstitial cells, which correlates with the fibrosis, tubular atrophy and oxidative stress observed in NPHS1 kidneys. Valkuaisvirtsaisuutta (proteinuriaa) aiheuttavat munuaissairaudet ovat lasten nefrologian keskeisin ongelma. Vaikea proteinuria saa aikaan nefroottisen oireyhtymän, ja jatkuva valkuaisvirtsaisuus johtaa munuaisen vähittäiseen tuhoutumiseen. Suomalaistyyppinen synnynnäinen nefroosi (CNF, NPHS1) on suomalaiseen tautiperimään kuuluva peittyvästi periytyvä sairaus, joka aikaansaa lapselle voimakkaan proteinurian jo vastasyntyneenä johtaen kuolemaan lapsuusiässä ilman munuaisensiirtoa. Taudin aiheuttaa geenivirhe, joka johtaa nefriini-proteiinin puutteeseen munuaiskeräsen kapillaariseinämässä. NPHS1-tautia pidetään vaikean nefroosin mallitautina, sillä se oli ensimmäisiä sairauksia, joissa valkuaisvirtsaisuuden syntymekanismia opittiin tuntemaan molekyylitasolla. Tässä väitöskirjatyössä tutkittiin NPHS1-munuaisten tuhoutumiseen johtavia keskeisiä solu- ja molekyylitason muutoksia. Työssä määritettiin munuaiskeräsen hiussuonten endoteelisolujen rakennetta ja proteiinien ilmentymisen muutoksia sekä munuaistiehyitä ympäröivien hiussuonten osuutta NPHS1-taudin etenemisessä. Työssä kartoitettiin myös munuaiskerästen vaurion etenemiseen vaikuttavien keskeisimpien välittäjäaineiden sekä niiden reseptoreiden ilmentymistä NPHS1-munuaisissa sekä proteiini- että geenitasolla. Tutkimukset osoittivat, että munuaiskerästen tukisolujen (mesangium) laajeneminen NPHS1-munuaisissa johtui niiden liiallisesta jakaantumisesta sekä soluväliaineen (pääasiassa kollageeni IV:n) lisääntymisestä. Mesangiumsolujen fenotyyppi säilyi melko normaalina, mutta laajentumiseen liittyi kapillaarien ahtautuminen ja vähentynyt hapensaanti. Pieniä paikallisia vaurioita lukuunottamatta NPHS1-potilaiden munuaiskerästen endoteelisolut olivat kokonaisuudessaan melko hyvin säilyneitä, eikä merkittäviä vaurioon viittaavia merkkejä ollut havaittavissa. Munuaistiehyitä ympäröivien hiussuonten lukumäärä ja halkaisija olivat pienentyneet NPHS1-munuaisissa aiheuttaen ympäröivään munuaiskudokseen hapenpuutetta, mikä todennäköisesti on merkittäviä tekijä NPHS1-munuaisten fibrotisoitumisessa. Työssämme myös havaittiin, että reniini-angiotensiini systeemin keskeisimmän proteiinin, angiotensiini II:n, ilmentyminen oli lisääntynyt NPHS1-munuaisissa. NPHS1-munuaisten havaittiin kärsivän myös oksidatiivisesta stressistä, josta osoituksena reaktiiviset happiyhdisteet ja lipidien peroksidaatio lisääntyivät sekä antioksidatiivisten entsyymien aktiivisuus väheni. Tästä olivat vastuussa ennen kaikkea vaurioituvaan munuaiseen kertyvät tulehdussolut. Tutkimuksen tulokset lisäävät tietämystämme proteinuriaan liittyvästä munuaisvaurion etenemisestä ja edesauttavat tähän liittyvää lääkekehitystyötä.
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron-induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron-induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms.
    Nature Reviews Nephrology 05/2013; DOI:10.1038/nrneph.2013.98 · 8.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of our study was to evaluate the correlation of polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and endothelial nitric oxide synthase (eNOS) genes and the development and prognostic implications for immunoglobulin A nephropathy (IgAN)/membranous nephropathy (MN). A polymerase chain reaction was performed for the AGT, ACE, and eNOS genes, followed by DNA sequencing and statistical analysis. There was a difference in ACE gene type II and type I between the IgAN and MN groups (P < .05) and in eNOS gene TT type and T type between the IgAN and MN groups (P < .05 and P < .01). In the IgAN group, significant differences were observed between ACE gene polymorphism and the age group of 20 years or less, male sex group, with/without hematuria, and high blood urea nitrogen (BUN; P < .05 or P < .01); between AGT gene polymorphism and with/without hematuria, high BUN, and pathologic classification (P < .05 or P < .01); and between eNOS gene polymorphism and high BUN and pathologic classification (P < .05 or P < .01). However, in the MN group, significant differences were observed between ACE gene polymorphism and the degree of proteinuria and high BUN (P < .001 and P < .05), between AGT gene polymorphism and with/without hematuria (P < .05), and between eNOS gene polymorphism and the degree of proteinuria and high BUN (P < .05 and P < .01). The ACE, AGT, and eNOS genes were correlated with the development of renal function failure in IgAN, whereas the ACE and eNOS genes were associated with the degree of proteinuria and the development of renal function failure in MN.
    Human pathology 10/2013; 44(12). DOI:10.1016/j.humpath.2013.07.032 · 2.81 Impact Factor

Preview

Download
3 Downloads
Available from