High Prevalence of Autoantibodies to hLAMP-2 in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.
J Am Soc Nephrol. 2012 Feb 9;
Authors: Kain R, Tadema H, McKinney EF, Benharkou A, Brandes R, Peschel A, Hubert V, Feenstra T, Sengölge G, Stegeman C, Heeringa P, Lyons PA, Smith KG, Kallenberg C, Rees AJ
Abstract
The involvement of autoantibodies to human lysosome-associated membrane protein-2 (hLAMP-2) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is controversial because of the absence of confirmatory data subsequent to the initial reports of their high prevalence in this disease. We characterized three assays for anti-hLAMP-2 antibodies: ELISA and Western blotting assays using unglycosylated recombinant hLAMP-2 expressed in Escherichia coli, and an indirect immunofluorescence assay using stably transfected ldlD cells that expressed glycosylated full-length hLAMP-2 on the plasma membrane. The assays detected autoantibodies to hLAMP-2 in human sera reproducibly and with comparable sensitivity and the assays gave the same results in 80.5% of the test panel of 40 selected positive and negative sera. In untreated patients at presentation, the frequencies of autoantibodies to LAMP-2 were 89%, 91%, and 80%, respectively, among three groups of patients with ANCA-associated vasculitis from Vienna, Austria (n=19); Groningen, the Netherlands (n=50) and Cambridge, United Kingdom (n=53). Prevalence of LAMP-2 autoantibodies was similar in both those with myeloperoxidase-ANCA and proteinase 3-ANCA. Furthermore, we detected LAMP-2 autoantibodies in two ANCA-negative patients. LAMP-2 autoantibodies rapidly became undetectable after the initiation of immunosuppressive treatment and frequently became detectable again during clinical relapse. We conclude that when robust assays are used, circulating autoantibodies to hLAMP-2 can be detected in most European patients with ANCA-associated vasculitis. Large-scale prospective studies are now needed to determine whether they are pathogenic or merely an epiphenomenon.
PMID: 22323643 [PubMed - as supplied by publisher]
Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension.
J Am Soc Nephrol. 2012 Feb 9;
Authors: Stec DE, Drummond HA, Gousette MU, Storm MV, Abraham NG, Csongradi E
Abstract
Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (139±3 versus 153±2 mmHg in the transgenic and control mice, respectively; P<0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption.
PMID: 22323644 [PubMed - as supplied by publisher]
Although there is a perception that the use of peritoneal dialysis is declining worldwide, compilations of global data are unavailable to test this hypothesis. We assessed longitudinal trends in the use of peritoneal dialysis from 1997 to 2008 in 130 countries. The preferred data sources were renal registries, followed by nephrology societies, health ministries, academic centers, national experts, and industry affiliates. In 2008, there were approximately 196,000 peritoneal dialysis patients worldwide, representing 11% of the dialysis population. In total, 59% were treated in developing countries and 41% in developed countries. Over 12 years, the number of peritoneal dialysis patients increased in developing countries by 24.9 patients per million population and in developed countries by 21.8 per million population. The proportion of all dialysis patients treated with peritoneal dialysis did not change in developing countries but significantly declined in developed countries by 5.3%. The use of automated peritoneal dialysis increased by 14.5% in developing countries and by 30.3% in developed countries. In summary, the number of patients treated with peritoneal dialysis rose worldwide from 1997 to 2008, with a 2.5-fold increase in the prevalence of peritoneal dialysis patients in developing countries. The proportion of all dialysis patients treated with this modality continues to decline in developed countries.
PMID: 22302194 [PubMed - as supplied by publisher]
Sonic Hedgehog Signaling Mediates Epithelial-Mesenchymal Communication and Promotes Renal Fibrosis.
J Am Soc Nephrol. 2012 Feb 2;
Authors: Ding H, Zhou D, Hao S, Zhou L, He W, Nie J, Hou FF, Liu Y
Abstract
Sonic hedgehog (Shh) signaling is a developmental signal cascade that plays an essential role in regulating embryogenesis and tissue homeostasis. Here, we investigated the potential role of Shh signaling in renal interstitial fibrogenesis. Ureteral obstruction induced Shh, predominantly in the renal tubular epithelium of the fibrotic kidneys. Using Gli1(lacZ) knock-in mice, we identified renal interstitial fibroblasts as Shh-responding cells. In cultured renal fibroblasts, recombinant Shh protein activated Gli1 and induced α-smooth muscle actin (α-SMA), desmin, fibronectin, and collagen I expression, suggesting that Shh signaling promotes myofibroblast activation and matrix production. Blockade of Shh signaling with cyclopamine abolished the Shh-mediated induction of Gli1, Snail1, α-SMA, fibronectin, and collagen I. In vivo, the kidneys of Gli1-deficient mice were protected against the development of interstitial fibrosis after obstructive injury. In wild-type mice, cyclopamine did not affect renal Shh expression but did inhibit induction of Gli1, Snail1, and α-SMA. In addition, cyclopamine reduced matrix expression and mitigated fibrotic lesions. These results suggest that tubule-derived Shh mediates epithelial-mesenchymal communication by targeting interstitial fibroblasts after kidney injury. We conclude that Shh/Gli1 signaling plays a critical role in promoting fibroblast activation, production of extracellular matrix, and development of renal interstitial fibrosis.
PMID: 22302193 [PubMed - as supplied by publisher]
MicroRNAs (miRNAs) are a group of small, noncoding RNAs that act as novel regulators of gene expression through the post-transcriptional repression of their target mRNAs. miRNAs have been implicated in diverse biologic processes, and it is estimated that up to half of all transcripts are regulated by miRNAs. Recent studies also demonstrate a critical role for miRNAs in renal development, physiology, and pathophysiology. Understanding the function of miRNAs in the kidney may lead to innovative approaches to renal disease.
PMID: 22302196 [PubMed - as supplied by publisher]
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