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1.
Am J Physiol Renal Physiol ; 321(5): F600-F616, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34541901

RESUMEN

Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101-F1111, 2017; Löwen J, Gröne E, Gröne HJ, Kriz W. Am J Physiol Renal Physiol 317: F399-F410, 2019), we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulointerstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerged from two defects: 1) increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium and 2) a defect of glomerular vessels consisting of increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of accumulated worn-out GBM material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule (BC) to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally intact podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulotubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myofibroblasts resulting in interstitial fibrosis.NEW & NOTEWORTHY Based on analysis of 918 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman's capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.


Asunto(s)
Nefropatías Diabéticas/patología , Glomerulonefritis/patología , Nefronas/patología , Biopsia , Cápsula Glomerular/patología , Capilares/patología , Permeabilidad Capilar , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Células Endoteliales/patología , Fibrosis , Membrana Basal Glomerular/patología , Glomerulonefritis/metabolismo , Humanos , Microscopía Electrónica de Transmisión , Neovascularización Patológica , Nefronas/metabolismo , Nefronas/ultraestructura , Podocitos/patología
2.
Kidney Int ; 97(2): 289-303, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31882173

RESUMEN

Systemic lupus erythematosus (SLE) is an autoimmune disease and lupus nephritis is a major risk factor for morbidity and mortality. Notch-3 signaling induced by membrane-bound or soluble ligands such as YB-1 constitutes an evolutionarily conserved pathway that determines major decisions in cell fate. Mass spectrometry of extracellular YB-1 in sera from patients with SLE and lupus-prone mice revealed specific post-translational guanidinylation of two lysine residues within the highly conserved cold-shock domain of YB-1 (YB-1-G). These modifications highly correlated with SLE disease activity, especially in patients with lupus nephritis and resulted in enhanced activation of Notch-3 signaling in T lymphocytes. The importance of YB-1:Notch-3 interaction in T cells was further evidenced by increased interleukin (Il)10 expression following YB-1-G stimulation and detection of both, YB-1-G and Notch-3, in kidneys of MRL.lpr mice by mass spectrometry imaging. Notch-3 expression and activation was significantly up-regulated in kidneys of 20-week-old MRL.lpr mice. Notably, lupus-prone mice with constitutional Notch-3 depletion (B6.Faslpr/lprNotch3-/-) exhibited an aggravated lupus phenotype with significantly increased mortality, enlarged lymphoid organs and aggravated nephritis. Additionally, these mice displayed fewer regulatory T cells and reduced amounts of anti-inflammatory IL-10. Thus, our results indicate that the YB-1:Notch-3 axis exerts protective effects in SLE and that Notch-3 deficiency exacerbates the SLE phenotype.


Asunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Receptor Notch3/metabolismo , Factores de Transcripción/metabolismo , Animales , Humanos , Lupus Eritematoso Sistémico/complicaciones , Ratones , Ratones Endogámicos MRL lpr , Transducción de Señal , Linfocitos T Reguladores
3.
Am J Physiol Renal Physiol ; 317(2): F399-F410, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31141396

RESUMEN

As shown in our previous paper (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101-F1111, 2017), mesangial matrix expansion in diabetic nephropathy (DN) results for a major part from the accumulation of worn-out undegraded glomerular basement membrane material. Here, based on the reevaluation of >900 biopsies of DN, we show that this process continues with the progression of the disease finally leading to the herniation of the matrix-overloaded tuft through the glomerular entrance to the outside. This leads to severe changes in the glomerular surroundings, including a dissociation of the juxtaglomerular apparatus with displacement of the macula densa. The herniation is associated with a prominent outgrowth of glomerular vessels from the tuft. Mostly, these aberrant vessels are an abnormal type of arteriole with frequent intramural insudations of plasma. They spread into glomerular surroundings extending in intertubular and periglomerular spaces. Their formation is associated with elevated mRNA levels of vascular endothelial growth factor-A, angiopoietins 1 and 2, and the corresponding receptors. Functionally, these processes seem to compromise tubuloglomerular feedback-related functions and may be one factor why Na+-glucose cotransporter-2 inhibitors are not effective in advanced stages of DN.


Asunto(s)
Arteriolas/patología , Nefropatías Diabéticas/patología , Mesangio Glomerular/irrigación sanguínea , Aparato Yuxtaglomerular/irrigación sanguínea , Neovascularización Patológica , Angiopoyetina 1/genética , Angiopoyetina 1/metabolismo , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Arteriolas/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Humanos , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
4.
Clin Immunol ; 194: 67-74, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30018024

RESUMEN

Calcineurin inhibitors (CNIs) are a cornerstone of the current treatment in solid organ transplantation and autoimmune disease. However, CNIs also bear deleterious effects as they cause glomerular and tubulointerstitial fibrosis in the kidney. We recently identified Y-box protein-1 (YB-1) as a novel downstream effector of CNI-signaling in the cytoplasm of glomerular cells. In the present study, we corroborate the pro-fibrotic role of YB-1 in glomeruli of patients under CNI-treatment. Such effects in glomeruli are significantly mitigated in CNI-treated mice with half-normal YB-1 expression (Yb1+/-). Surprisingly, in the tubulointerstitium we observe an opposite role of the CNI-YB-1 axis. Here, YB-1 is predominantly located to the nuclei and represses transcription of several extracellular matrix genes. Consistently, CNI-treatment in Yb1+/- mice markedly increases pro-fibrotic changes in the tubulointerstitium. In summary, our data provide evidence that fibrotic CNI-induced YB-1 effects in glomerular cells need to be contrasted with beneficial anti-fibrotic effects in the tubulointerstitium.


Asunto(s)
Inhibidores de la Calcineurina/efectos adversos , Fibrosis/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Factores de Transcripción/metabolismo , Animales , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Femenino , Fibrosis/genética , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/genética , Glomérulos Renales/metabolismo , Trasplante de Riñón/métodos , Ratones , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genética
5.
JCI Insight ; 3(11)2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29875315

RESUMEN

Lupus nephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Among the different types of lupus nephritis, intracapillary immune complex (IC) deposition and accumulation of monocytes are hallmarks of lupus nephritis class III and IV. The relevance of intracapillary ICs in terms of monocyte recruitment and activation, as well as the nature and function of these monocytes are not well understood. For the early focal form of lupus nephritis (class III) we demonstrate a selective accumulation of the proinflammatory population of 6-sulfo LacNAc+ (slan) monocytes (slanMo), which locally expressed TNF-α. Immobilized ICs induced a direct recruitment of slanMo from the microcirculation via interaction with Fc γ receptor IIIA (CD16). Interestingly, intravenous immunoglobulins blocked CD16 and prevented cell recruitment. Engagement of immobilized ICs by slanMo induced the production of neutrophil-attracting chemokine CXCL2 as well as TNF-α, which in a forward feedback loop stimulated endothelial cells to produce the slanMo-recruiting chemokine CX3CL1 (fractalkine). In conclusion, we observed that expression of CD16 equips slanMo with a unique capacity to orchestrate early IC-induced inflammatory responses in glomeruli and identified slanMo as a pathogenic proinflammatory cell type in lupus nephritis.


Asunto(s)
Amino Azúcares/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Glomérulos Renales/inmunología , Nefritis Lúpica/inmunología , Monocitos/inmunología , Amino Azúcares/metabolismo , Animales , Complejo Antígeno-Anticuerpo/administración & dosificación , Complejo Antígeno-Anticuerpo/metabolismo , Biopsia , Capilares/citología , Capilares/inmunología , Capilares/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Células Jurkat , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/patología , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/patología , Masculino , Ratones , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Cultivo Primario de Células , Receptores de IgG/antagonistas & inhibidores , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
6.
Pflugers Arch ; 469(7-8): 899-906, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28685176

RESUMEN

Chronic tubulointerstitial damage with tubular epithelial atrophy and interstitial fibrosis is the hallmark of chronic kidney disease (CKD) and a predictor for progression of CKD.Several experiments have now provided evidence that the Wnt signaling pathways are significantly contributing to atrophy and fibrosis; in contrast, it also has been shown that the Wnt system fosters regenerative processes in acute tubular injury.We now have demonstrated that Dickkopf 3 (DKK3) is an agonist for canonical Wnt signaling in CKD and fosters chronic fibrosing inflammation of the tubulointerstitial compartment. Genetic- and antibody-mediated inhibition of DKK3 leads to a pronounced improvement of tubular differentiation and a reduction in fibrosis.In addition, the secreted glycoprotein DKK3 can be used as a non-invasive urinary marker for the extent of CKD in man.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Insuficiencia Renal Crónica/metabolismo , Vía de Señalización Wnt , Proteínas Adaptadoras Transductoras de Señales , Animales , Quimiocinas , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Insuficiencia Renal Crónica/genética
7.
J Diabetes Complications ; 31(6): 1058-1065, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28325697

RESUMEN

BACKGROUND & AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) functions analogue to the receptor of advanced glycation end products, which has been implicated in the development of diabetic nephropathy (DN). We investigated the expression of ALCAM and its ligand S100B in patients with DN. METHODS: A total of 34 non-diabetic patients, 29 patients with type 2 diabetes and normal albuminuria and 107 patients with type 2 diabetes complicated with DN were assessed for serum concentration of soluble ALCAM (sALCAM) by ELISA. Expression of ALCAM and S100B in kidney histology from patients with DN was determined by immunohistochemistry. Cell expression of ALCAM and S100B was analyzed through confocal immunofluorescence microscopy. RESULTS: Serum concentration of sALCAM was increased in diabetic patients with DN compared to non-diabetic (59.85±14.99ng/ml vs. 126.88±66.45ng/ml, P<0.0001). Moreover sALCAM correlated positively with HbA1c (R=0.31, P<0.0001), as well as with the stages of chronic kidney disease and negatively correlated with eGFR (R=-0.20, P<0.05). In diabetic patients with normal albuminuria sALCAM was increased compared to patients with DN (126.88±66.45ng/ml vs. 197.50±37.17ng/ml, P<0.0001). In diabetic patients, ALCAM expression was significantly upregulated in both the glomeruli and tubules (P<0.001). ALCAM expression in the glomeruli correlated with presence of sclerosis (R=0.25, P<0.001) and localized mainly in the podocytes supporting the hypothesis that membrane bound ALCAM drives diabetic nephropathy and thus explaining sALCAM decrease in diabetic patients with DN. The expression of S100B was increased significantly in the glomeruli of diabetic patients (P<0.001), but not in the tubules. S100B was as well localized in the podocytes. CONCLUSIONS: This study identifies for the first time ALCAM as a potential mediator in the late complications of diabetes in the kidney.


Asunto(s)
Antígenos CD/sangre , Biomarcadores/sangre , Moléculas de Adhesión Celular Neuronal/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/diagnóstico , Proteínas Fetales/sangre , Adulto , Anciano , Antígenos CD/análisis , Antígenos CD/fisiología , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/análisis , Moléculas de Adhesión Celular Neuronal/fisiología , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Femenino , Proteínas Fetales/análisis , Proteínas Fetales/fisiología , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico
8.
Am J Physiol Renal Physiol ; 312(6): F1101-F1111, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28228399

RESUMEN

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (α3 and α5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the α1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes.


Asunto(s)
Nefropatías Diabéticas/patología , Membrana Basal Glomerular/ultraestructura , Mesangio Glomerular/ultraestructura , Podocitos/ultraestructura , Agrina/análisis , Autoantígenos/análisis , Biopsia , Microambiente Celular , Colágeno Tipo IV/análisis , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Membrana Basal Glomerular/química , Mesangio Glomerular/química , Proteoglicanos de Heparán Sulfato/análisis , Humanos , Inmunohistoquímica , Microscopía Electrónica de Transmisión , Podocitos/química , Esclerosis
9.
J Inflamm (Lond) ; 14: 3, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28167864

RESUMEN

BACKGROUND: Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. METHODS: Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. RESULTS: Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. CONCLUSION: In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined.

10.
J Am Soc Nephrol ; 26(11): 2789-99, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26015455

RESUMEN

Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undefined. Here, we investigated the role of TM-dependent aPC generation and therapeutic aPC application in a murine renal IRI model and in an in vitro hypoxia and reoxygenation (HR) model using proximal tubular cells. In renal IRI, endogenous aPC levels were reduced. Genetic or therapeutic reconstitution of aPC efficiently ameliorated renal IRI independently of its anticoagulant properties. In tubular cells, cytoprotective aPC signaling was mediated through protease activated receptor-1- and endothelial protein C receptor-dependent regulation of the cold-shock protein Y-box binding protein-1 (YB-1). The mature 50 kD form of YB-1 was required for the nephro- and cytoprotective effects of aPC in vivo and in vitro, respectively. Reduction of mature YB-1 and K48-linked ubiquitination of YB-1 was prevented by aPC after renal IRI or tubular HR injury. aPC preserved the interaction of YB-1 with the deubiquitinating enzyme otubain-1 and maintained expression of otubain-1, which was required to reduce K48-linked YB-1 ubiquitination and to stabilize the 50 kD form of YB-1 after renal IRI and tubular HR injury. These data link the cyto- and nephroprotective effects of aPC with the ubiquitin-proteasome system and identify YB-1 as a novel intracellular target of aPC. These insights may provide new impetus for translational efforts aiming to restrict renal IRI.


Asunto(s)
Riñón/patología , Proteína C/metabolismo , Daño por Reperfusión/patología , Factores de Transcripción/metabolismo , Ubiquitinación , Alelos , Animales , Anticoagulantes/química , Cruzamientos Genéticos , Cisteína Endopeptidasas/genética , Modelos Animales de Enfermedad , Exones , Hipoxia/patología , Túbulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxígeno/química , Transducción de Señal , Trombosis/metabolismo
11.
Transplantation ; 99(2): 331-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25594551

RESUMEN

BACKGROUND: Renal transplant glomerulitis (G) is associated with acute antibody-mediated rejection (ABMR) in the presence of donor-specific antibodies. However, the long-term prognosis of isolated G (isG) in the absence of donor-specific antibodies or G in combination with T cell-mediated rejection (TCMR) remains unexplored. METHODS: Seventy recipients with G were included in this retrospective study and subdivided into 3 groups: isG, G with TCMR (G+TCMR), and G with acute ABMR. The control groups were: patients with TCMR Banff type I or II without G (TCMR) and patients without rejection (NR). Kaplan-Meier death-censored survival plots and Cox regression were used to analyze graft survival. The combined graft survival endpoint was defined as a return to dialysis or estimated glomerular filtration rate less than 15 mL/min/1.73 m. The median follow-up was 37 (14; 77) months from biopsy. RESULTS: Graft survival was significantly lower in patients with G than in the NR and TCMR groups. No significant differences were observed among the isG, G+TCMR, and ABMR groups. Graft survival was lower in the G+TCMR group than in the TCMR group. Glomerulitis was independently associated with the risk of adverse graft outcome in a multivariate Cox regression model adjusted for other confounders (hazard ratio, 4.52 [95% confidence interval, 2.37-8.68] vs controls; P<0.001). CONCLUSIONS: Glomerulitis is strongly associated with increased risk of graft failure. Graft survival in patients with isG that do not meet the Banff criteria for acute/active ABMR and in patients with G accompanying TCMR is comparable to the ABMR group.


Asunto(s)
Glomerulonefritis/inmunología , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Adulto , Aloinjertos , Anticuerpos/sangre , Distribución de Chi-Cuadrado , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis/diagnóstico , Glomerulonefritis/mortalidad , Glomerulonefritis/fisiopatología , Glomerulonefritis/terapia , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/mortalidad , Rechazo de Injerto/fisiopatología , Rechazo de Injerto/terapia , Humanos , Estimación de Kaplan-Meier , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Diálisis Renal , Estudios Retrospectivos , Factores de Riesgo , Linfocitos T/inmunología , Factores de Tiempo
12.
PLoS One ; 9(8): e103413, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25133636

RESUMEN

IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN.


Asunto(s)
Glomerulonefritis por IGA/metabolismo , Transcriptoma , Corticoesteroides/uso terapéutico , Adulto , Simulación por Computador , Evaluación Preclínica de Medicamentos , Femenino , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Humanos , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neovascularización Patológica/metabolismo , Fenotipo , Adulto Joven
13.
J Pathol ; 234(1): 120-33, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24909663

RESUMEN

The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2-associated kidney failure (n = 11, aged 22-44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31-17.60) mg/dl, lactate dehydrogenase 1944 (753-2792) U/l, platelets 33 (19-124)/nl and haemoglobin 6.2 (5.2-7.8) g/dl; median (range)], all patients were discharged after 33 (range 19-43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84-2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66-1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2-mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only.


Asunto(s)
Lesión Renal Aguda/patología , Infecciones por Escherichia coli/patología , Toxina Shiga II/metabolismo , Escherichia coli Shiga-Toxigénica/patogenicidad , Lesión Renal Aguda/microbiología , Lesión Renal Aguda/terapia , Adulto , Animales , Biopsia , Línea Celular , Estudios de Cohortes , Creatinina/metabolismo , Modelos Animales de Enfermedad , Epitelio/microbiología , Epitelio/patología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/terapia , Femenino , Globósidos/metabolismo , Humanos , Túbulos Renales/microbiología , Túbulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Toxina Shiga II/genética , Microangiopatías Trombóticas , Resultado del Tratamiento , Adulto Joven
14.
Am J Pathol ; 182(3): 727-41, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23318573

RESUMEN

Dyslipidemia is a frequent component of the metabolic disorder of diabetic patients contributing to organ damage. Herein, in low-density lipoprotein receptor-deficient hyperlipidemic and streptozotozin-induced diabetic mice, hyperglycemia and hyperlipidemia acted reciprocally, accentuating renal injury and altering renal function. In hyperglycemic-hyperlipidemic kidneys, the accumulation of Tip47-positive lipid droplets in glomeruli, tubular epithelia, and macrophages was accompanied by the concomitant presence of the oxidative stress markers xanthine oxidoreductase and nitrotyrosine, findings that could also be evidenced in renal biopsy samples of diabetic patients. As liver X receptors (LXRα,ß) regulate genes linked to lipid and carbohydrate homeostasis and inhibit inflammatory gene expression in macrophages, the effects of systemic and macrophage-specific LXR activation were analyzed on renal damage in hyperlipidemic-hyperglycemic mice. LXR stimulation by GW3965 up-regulated genes involved in cholesterol efflux and down-regulated proinflammatory/profibrotic cytokines, inhibiting the pathomorphology of diabetic nephropathy, renal lipid accumulation, and improving renal function. Xanthine oxidoreductase and nitrotyrosine levels were reduced. In macrophages, GW3965 or LXRα overexpression significantly suppressed glycated or acetylated low-density lipoprotein-induced cytokines and reactive oxygen species. Specifically, in mice, transgenic expression of LXRα in macrophages significantly ameliorated hyperlipidemic-hyperglycemic nephropathy. The results demonstrate the presence of lipid droplet-induced oxidative mechanisms and the pathophysiologic role of macrophages in diabetic kidneys and indicate the potent regulatory role of LXRs in preventing renal damage in diabetes.


Asunto(s)
Hiperglucemia/patología , Riñón/patología , Metabolismo de los Lípidos , Receptores Nucleares Huérfanos/metabolismo , Animales , Benzoatos/farmacología , Bencilaminas/farmacología , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Células Endoteliales/ultraestructura , Fibrosis , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/genética , Hiperglucemia/fisiopatología , Hiperlipidemias/complicaciones , Hiperlipidemias/genética , Hiperlipidemias/patología , Hiperlipidemias/fisiopatología , Inflamación/patología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Riñón/ultraestructura , Pruebas de Función Renal , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Receptores X del Hígado , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Células Mesangiales/efectos de los fármacos , Células Mesangiales/patología , Células Mesangiales/ultraestructura , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Podocitos/ultraestructura
15.
Kidney Int ; 81(1): 100-11, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21918500

RESUMEN

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-ß mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1ß or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.


Asunto(s)
Virus BK , Inmunidad Innata , Enfermedades Renales/etiología , Enfermedades Renales/inmunología , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Virus BK/inmunología , Virus BK/patogenicidad , Secuencia de Bases , Células Cultivadas , Quimiocinas/genética , Citocinas/genética , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , Técnicas de Silenciamiento del Gen , Humanos , Enfermedades Renales/genética , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/genética , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Receptores Inmunológicos , Receptor Toll-Like 3/antagonistas & inhibidores , Receptor Toll-Like 3/genética , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/genética
16.
Blood ; 119(3): 874-83, 2012 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-22117049

RESUMEN

The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies.


Asunto(s)
Apoptosis , Citoprotección , Podocitos/metabolismo , Proteína C/metabolismo , Receptor PAR-1/metabolismo , Receptores de Trombina/metabolismo , Animales , Anticoagulantes/metabolismo , Comunicación Celular , Células Cultivadas , Humanos , Glomérulos Renales/citología , Glomérulos Renales/metabolismo , Lipopolisacáridos/farmacología , Microdominios de Membrana , Ratones , Podocitos/efectos de los fármacos , Podocitos/patología , Multimerización de Proteína , Transducción de Señal , Trombina
17.
Dtsch Med Wochenschr ; 134(44): 2231, 2009 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-19847734

RESUMEN

HISTORY AND ADMISSION FINDINGS: A 44-year-old male and his 40-year-old wife, both previously in good health, were admitted for abdominal pain, diarrhea, vomiting, severe headache, and oliguria after ingestion of wild mushrooms two weeks earlier. Physical examination revealed costo-vertebral-angular tenderness in the husband and abdominal tenderness in both patients. INVESTIGATIONS: Laboratory showed acute renal injury with markedly increased serum concentrations of creatine and urea. On abdominal ultrasound, the kidneys were slightly increased in size with echogenic parenchyma and prominent medullary pyramids. Signs of an immunological or infectious etiology were missing. Histological investigation of the renal biopsy showed acute interstitial nephritis with marked tubular damage in both cases. DIAGNOSIS, TREATMENT AND COURSE: History and histological findings were consistent with Orellanus syndrome following ingestion of mushrooms of the Cortinarius species. In both patients, haemodialysis was initiated. In the husband, dialysis was discontinued on day 8 and a follow-up visit after one month revealed stage 5 chronic kidney disease. In the wife, continuation of haemodialysis in an ambulatory setting required implantation of a temporary vascular catheter. CONCLUSIONS: In cases of acute renal injury of unknown origin, ingestion of mushrooms of the Cortinarius species should be included in the differential diagnoses. In particular, initial gastrointestinal complaints may point to this rare differential diagnosis.


Asunto(s)
Cortinarius , Túbulos Renales/patología , Intoxicación por Setas/complicaciones , Nefritis Intersticial/etiología , Dolor Abdominal , Enfermedad Aguda , Adulto , Biopsia , Creatinina/sangre , Diagnóstico Diferencial , Diarrea , Femenino , Cefalea , Humanos , Riñón/diagnóstico por imagen , Masculino , Intoxicación por Setas/diagnóstico , Nefritis Intersticial/patología , Nefritis Intersticial/terapia , Oliguria , Diálisis Renal , Ultrasonografía , Urea/sangre , Vómitos
18.
J Med Case Rep ; 3: 6839, 2009 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-19830127

RESUMEN

INTRODUCTION: Impaired renal function and/or pre-existing atherosclerosis in the deceased donor increase the risk of delayed graft function and impaired long-term renal function in kidney transplant recipients. CASE PRESENTATION: We report delayed graft function occurring simultaneously in two kidney transplant recipients, aged 57-years-old and 39-years-old, who received renal allografts from the same deceased donor. The 62-year-old donor died of cardiac arrest during an asthmatic state. Renal-allograft biopsies performed in both kidney recipients because of delayed graft function revealed cholesterol-crystal embolism. An empiric statin therapy in addition to low-dose acetylsalicylic acid was initiated. After 10 and 6 hemodialysis sessions every 48 hours, respectively, both renal allografts started to function. Glomerular filtration rates at discharge were 26 ml/min/1.73m(2) and 23.9 ml/min/1.73m(2), and remained stable in follow-up examinations. Possible donor and surgical procedure-dependent causes for cholesterol-crystal embolism are discussed. CONCLUSION: Cholesterol-crystal embolism should be considered as a cause for delayed graft function and long-term impaired renal allograft function, especially in the older donor population.

19.
Shock ; 32(2): 159-63, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19008785

RESUMEN

Statins, which are effective lipid-lowering drugs, also possess anti-inflammatory potential. However, circulating lipoproteins may also play a protective role during acute inflammatory diseases because of their ability to bind bacterial toxins. Low cholesterol levels have been reported in inflammatory conditions, and plasma cholesterol concentrations inversely correlate with severity and clinical outcome in septic patients. It is thus paradoxical that statins, which drastically reduce circulating cholesterol levels, should be beneficial in patients with inflammatory disease who are already hypocholesterolemic. We investigated the effect of simvastatin on LPS-induced nuclear factor kappaB (NF-kappaB) activation, TNF release, and mortality in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans. In the present study, simvastatin reduced circulating total and low-density lipoprotein cholesterol levels by 68% and 76%, respectively, and LPS-induced mortality from 73% to 20%. This reduction was accompanied by a significant reduction of NF-kappaB activation in the liver tissue, splenocytes, and plasma TNF levels by about 80%, 50%, and 77%, respectively. Our data suggest that simvastatin, despite lowering circulating low-density lipoprotein cholesterol, decreased LPS toxicity by reduction of NF-kappaB activation and subsequent release of TNF by modulating 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and therefore deserves consideration as a possible adjuvant therapy in acute inflammatory disease.


Asunto(s)
Anticolesterolemiantes/farmacología , LDL-Colesterol/inmunología , Endotoxinas/toxicidad , FN-kappa B/inmunología , Sepsis/tratamiento farmacológico , Simvastatina/farmacología , Animales , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Modelos Animales de Enfermedad , Cobayas , Humanos , Hidroximetilglutaril-CoA Reductasas/inmunología , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hígado/inmunología , Hígado/metabolismo , Masculino , FN-kappa B/metabolismo , Sepsis/sangre , Sepsis/inducido químicamente , Sepsis/inmunología , Simvastatina/uso terapéutico , Factores de Necrosis Tumoral/inmunología , Factores de Necrosis Tumoral/metabolismo
20.
NDT Plus ; 2(4): 314-7, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25984026
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