In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-kB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.
Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti-glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NETrelated histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.
Kidney remodeling is a response to intrinsic or extrinsic triggers of kidney injury. Injury initiates a set of universal response programs that were positively selected through evolution to control potentially life-threatening dangers and to regain homeostasis, including tissue repair. These danger control programs are (i) clotting, to control the risk of bleeding; (ii) inflammation, to control the risk of infection; (iii) epithelial repair; (iv) mesenchymal repair; and (v) scar resolution or minimization. In this review we focus on the role of mesangial cells in glomerular disorders and how their behaviors follow these danger control programs. We review the role of mesangial cells in glomerular coagulation and fibrinolysis, as well as their role in triggering glomerular inflammation and mesangioproliferative disorders. Furthermore, we discuss how the mesangium self-repairs, how podocyte injury triggers a "mesenchymal healing"-kind of response that leads to glomerular fibrosis and sclerosis. Thus, we can better appreciate the contribution of mesangial cells to glomerular pathology when we understand their behavior as an attempt to support the evolutionally conserved universal danger control programs. However, these mechanisms often result in maladaptive processes that destroy the complex glomerular ultrastructure rather than help to regain tissue homeostasis.
Nitric oxide (NO) modulates renal blood flow (RBF) and kidney function and is involved in blood pressure (BP) regulation predominantly via stimulation of the NO-sensitive guanylyl cyclase (NO-GC), existing in two isoforms, NO-GC1 and NO-GC2. Here, we used isoform-specific knockout (KO) mice and investigated their contribution to renal hemodynamics under normotensive and angiotensin II-induced hypertensive conditions. Stimulation of the NO-GCs by S-nitrosoglutathione (GSNO) reduced BP in normotensive and hypertensive wildtype (WT) and NO-GC2-KO mice more efficiently than in NO-GC1-KO. NO-induced increase of RBF in normotensive mice did not differ between the genotypes, but the respective increase under hypertensive conditions was impaired in NO-GC1-KO. Similarly, inhibition of endogenous NO increased BP and reduced RBF to a lesser extent in NO-GC1-KO than in NO-GC2-KO. These findings indicate NO-GC1 as a target of NO to normalize RBF in hypertension. As these effects were not completely abolished in NO-GC1-KO and renal cyclic guanosine monophosphate (cGMP) levels were decreased in both NO-GC1-KO and NO-GC2-KO, the results suggest an additional contribution of NO-GC2. Hence, NO-GC1 plays a predominant role in the regulation of BP and RBF, especially in hypertension. However, renal NO-GC2 appears to compensate the loss of NO-GC1, and is able to regulate renal hemodynamics under physiological conditions.
Diabetes-associated emergencies are frequent and include hyperglycemic states, such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) as well as hypoglycemia (hypoglycemic coma) and metabolic disturbances that are unrelated to pathological blood glucose aberrations (lactic acidosis). Knowledge of the respective risk situations, key signs and symptoms as well as early detection, special aspects of intensive care treatment and procedures for the prevention of these diabetes emergency cases is a must not only for the duty doctor in intensive care but also for diabetologists, internists and family doctors in the outpatient situation. The basic facts on these issues are presented in this continuing medical education (CME) article in a didactically clear form.
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