Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future.

/pdf/pathophysiology-of-acute-kidney-injury-57ami3f8ia.pdf

Pathophysiology of Acute Kidney Injury

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low resistance. In this review, we discuss the diversity, history and the various mechanisms of action of AMPs. Although many AMPs have reached clinical trials, to date not many have been approved by the US Food and Drug Administration (FDA) due to issues with toxicity, protease cleavage and short half-life. Some of the recent strategies developed to improve the activity and biocompatibility of AMPs, such as chemical modifications and the use of delivery systems, are also reviewed in this article.

/pdf/antimicrobial-peptides-diversity-mechanism-of-action-and-598cs99v90.pdf

Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

/pdf/dysfunctional-hdl-and-atherosclerotic-cardiovascular-disease-3570yicbs9.pdf

Dysfunctional HDL and atherosclerotic cardiovascular disease

Background
Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.

/pdf/a-prospective-phase-ii-trial-exploring-the-association-3auvzf3yom.pdf

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

The susceptibility or resistance of tubular epithelial cells (TEC) to apoptosis is pivotal to the long-term maintenance of kidney function following episodes of inflammation, such as graft rejectio...

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00341.2005

Nitric oxide induces apoptosis in renal tubular epithelial cells through activation of caspase-8.

Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan to N-formyl kynurenine and has a proapoptotic role in renal tubular epithelial cells (TEC) in response to IFN-γ and TNF-α in vitro. TEC prod...

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00567.2007

Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury

Exposure of renal tubular epithelial cells (TEC) to IFN-gamma/TNF-alpha leads to Fas/FasL-mediated self-injury, which contributes to allograft rejection. Indoleamine 2,3-dioxygenase (IDO) converts tryptophan to N-formyl-kynurenine and contributes to immune privilege in tissues by increasing Fas-mediated T cell apoptosis. However, renal expression of IDO and its role in promoting Fas-mediated TEC death have not been examined. IDO expression was analyzed by RT-PCR and Western blot. Apoptosis was measured by fluorescence-activated cell sorting analysis and terminal deoxytransferase-mediated dUTP nick end labeling. We demonstrated that functional IDO is expressed in TEC and is increased by IFN-gamma/TNF-alpha exposure. Increased IDO activity promoted TEC apoptosis, whereas inhibition of IDO by its specific inhibitor 1-methyl-d-tryptophan attenuated IFN-gamma/TNF-alpha-mediated TEC apoptosis and augmented TEC survival. Transgenic expression of IDO resulted in increased TEC apoptosis in the absence of proinflammatory cytokine exposure, supporting a central role for IDO in TEC injury. Inhibition of IDO-mediated TEC death by a caspase-8-specific inhibitor (Z-IETD-FMK), as well as the absence of an IDO effect in Fas-deficient and FasL-deficient TEC, supports a Fas/FasL-dependent, caspase-8-mediated mechanism for IDO-enhanced TEC death. These data suggest that renal IDO expression may be deleterious during renal inflammation, because it enhances TEC self-injury through Fas/FasL interactions. Thus attenuation of IDO may represent a novel strategy to promote kidney function following ischemia and renal allograft rejection.

Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells.

Decreased renal ischemia-reperfusion injury by IL-16 inactivation.

BACKGROUND Renal ischemia-reperfusion injury (IRI) largely contributes to kidney transplant dysfunction and acute kidney injury, but its pathogenesis is not fully understood. In this study, the role of transforming growth factor (TGF)-beta1 in renal IRI is investigated using TGF-beta1 deficient mice. METHOD Human renal tubular epithelial cells (TEC) line (HK-2) was used as an in vitro model, and cell apoptosis was determined by flow cytometric analysis. Renal IRI was induced in mice by clamping renal vein and artery for 45 min at 32 degrees C. RESULTS Here, we showed that in cultures of HK-2 cells, TGF-beta1 expression was up-regulated by tumor necrosis factor (TNF)-alpha. Neutralization of TGF-beta1 activity increased both spontaneous and TNF-alpha-mediated apoptosis, and knockdown of TGF-beta1 expression increased the sensitivity of cell apoptosis to TNF-alpha. In a mouse model of renal IRI, a deficiency in TGF-beta1 expression increased the severity of renal injury, as indicated by more severe renal tubular damage, higher levels of serum creatinine or blood urea nitrogen in TGF-beta1 deficient mice as compared with those in wild-type controls. Further experiments showed that the antiapoptosis of TGF-beta1 correlated with up-regulation of Bcl-2 in kidney cells. CONCLUSION Expression of TGF-beta1 in TECs, potentially induced by proinflammatory TNF-alpha, renders TECs resistance to cell death. In mice, TGF-beta1 deficiency results in more prone to IRI. These data imply that TGF-beta1 may act as a feedback survival factor in the resistance to kidney injury and maintenance of epithelium homeostasis.

Qiunong Guan

Papers

Nitric oxide induces apoptosis in renal tubular epithelial cells through activation of caspase-8.

Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury

Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells.

Decreased renal ischemia-reperfusion injury by IL-16 inactivation.

Expression of Transforming Growth Factor-β1 Limits Renal Ischemia-Reperfusion Injury