Atrial fibrillation: the beat is faster than the answers.
Kidney Int. 2012 Mar;81(5):432-3
Authors: Szczech LA
Abstract
The prevalence of atrial fibrillation is much greater among persons with end-stage renal disease (ESRD) than among the general population. While significant advances have been made recently in the treatment of atrial fibrillation in the general population, we know very little about the treatment of atrial fibrillation among those with ESRD. This Commentary explores gaps in our knowledge of how to treat this vulnerable and sick population.
Although older teaching suggested that patients who survived an episode of acute kidney injury (AKI) had a benign course, recent studies have demonstrated that AKI is strongly associated with increased risk for development of progressive chronic kidney disease (CKD) and longer-term mortality. Much as we understand that CKD predisposes to the development of AKI, we must recognize that the relationship is bidirectional and that our patients with AKI are at risk for chronic-on-acute kidney disease.
Tubular cell dedifferentiation and peritubular inflammation are coupled by the transcription regulator Id1 in renal fibrogenesis.
Kidney Int. 2012 Jan 25;
Authors: Li Y, Wen X, Liu Y
Abstract
During renal fibrogenesis, tubular epithelial-mesenchymal transition is closely associated with peritubular inflammation; however, it is not clear whether these two processes are connected. We previously identified the inhibitor of differentiation-1 (Id1), a dominant negative antagonist of basic helix-loop-helix transcription factors, as a major trigger of tubular cell dedifferentiation after injury. Id1 was induced selectively in degenerated proximal tubule and collecting duct epithelia after injury and was present in both the cytoplasm and nucleus, suggesting shuttling between these two compartments. Interestingly, the upregulation of Id1 was associated with peritubular inflammation in mouse and human nephropathies. In vitro, Id1 potentiated NF-κB signaling and augmented RANTES expression in kidney epithelial cells, which led to an enhanced recruitment of inflammatory cells. Id1 also induced Snail1 expression and triggered tubular epithelial dedifferentiation. In vivo, genetic ablation of Id1 in mice reduced peritubular inflammation and decreased tubular expression of RANTES following ureteral obstruction. Mice lacking Id1 were also protected against myofibroblast activation and matrix expression, leading to a reduced total collagen deposition in obstructive nephropathy. Thus, these results indicate that Id1 shuttles between nucleus and cytoplasm, and promotes peritubular inflammation and tubular epithelial dedifferentiation, suggesting that these two events are intrinsically coupled during renal fibrogenesis.Kidney International advance online publication, 25 January 2012; doi:10.1038/ki.2011.469.
PMID: 22278018 [PubMed - as supplied by publisher]
Mechanisms of the proteinuria induced by Rho GTPases.
Kidney Int. 2012 Jan 25;
Authors: Wang L, Ellis MJ, Gomez JA, Eisner W, Fennell W, Howell DN, Ruiz P, Fields TA, Spurney RF
Abstract
Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.Kidney International advance online publication, 25 January 2012; doi:10.1038/ki.2011.472.
PMID: 22278020 [PubMed - as supplied by publisher]
TWEAK (tumor necrosis factor-like weak inducer of apoptosis) activates CXCL16 expression during renal tubulointerstitial inflammation.
Kidney Int. 2012 Jan 25;
Authors: Izquierdo MC, Sanz AB, Mezzano S, Blanco J, Carrasco S, Sanchez-Niño MD, Benito-Martín A, Ruiz-Ortega M, Egido J, Ortiz A
Abstract
TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a TNF superfamily cytokine that activates the fibroblast growth factor-inducible 14 (Fn14) receptor. Transcriptional analysis of experimental kidney tubulointerstitial inflammation showed a correlation between an upregulation of the mRNA for the transmembrane chemokine CXCL16, a T-cell chemoattractant, and Fn14 activation. Exogenous TWEAK increased mouse kidney CXCL16 expression and T-lymphocyte infiltration in vivo, processes inhibited by the NF-κB inhibitor parthenolide. Tubular cell CXCL16 was increased in a nephrotoxic tubulointerstitial inflammation model and neutralizing anti-TWEAK antibodies decreased this CXCL16 expression and lymphocyte infiltration. In human kidney biopsies with tubulointerstitial inflammation, tubular cell CXCL16 and Fn14 expressions were associated with inflammatory infiltrates. TWEAK upregulated CXCL16 mRNA expression in cultured renal tubular cells in an NF-κB-dependent manner and increased soluble and cellular CXCL16 protein. CXCL16 modestly promoted the expression of cytokines in tubular cells expressing its receptor (CXCR6) and appeared to synergize with TWEAK to promote an inflammatory response; however, it did not modulate tubular cell proliferation or survival. Thus, TWEAK upregulates the expression of the chemokine CXCL16 in tubular epithelium and this may contribute to kidney tubulointerstitial inflammation.Kidney International advance online publication, 25 January 2012; doi:10.1038/ki.2011.475.
PMID: 22278019 [PubMed - as supplied by publisher]
Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2.
Kidney Int. 2012 Jan 25;
Authors: Jung M, Sola A, Hughes J, Kluth DC, Vinuesa E, Viñas JL, Pérez-Ladaga A, Hotter G
Abstract
Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow-derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1 h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10-mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10-mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.Kidney International advance online publication, 25 January 2012; doi:10.1038/ki.2011.446.
PMID: 22278021 [PubMed - as supplied by publisher]
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