Patterns of cell death.

Cell death takes two distinct forms, necrosis and apoptosis. Necrosis is a degenerative phenomenon that follows irreversible injury. Apoptosis, in contrast, appears to be an active process requiring protein synthesis for its execution; it is implicated in physiological regulation of tissue size, and, where it occurs pathologically, a homeostatic role for the death is often evident. Morphologically, apoptosis involves condensation of the nuclear chromatin and cytoplasm, fragmentation of the nucleus, and budding of the whole cell to produce membrane-bounded bodies in which organelles are initially intact. These bodies are disposed of by adjacent cells without inflammation. Biochemically, there is distinctive internucleosome cleavage of DNA in apoptosis, which is quite different from the random DNA degradation observed in necrosis

Uric acid heralds ischemic tissue injury to mobilize endothelial progenitor cells

Understanding the nature of endogenous mechanisms for mobilization of stem/progenitor cells is predicated on the identification of injury-induced substances that are released from a damaged organ and capable of producing a distant effect. Although different substances that mobilize endothelial progenitor cells (EPCs) have been proposed, their potential to signal injury and afford postischemic renoprotection and repair remains obscure. Uric acid (UA) is consistently overproduced by ischemic tissues and has been shown to exert immunomodulatory functions. It was hypothesized that UA and/or its precursors might serve as injury signals that are capable of mobilizing EPCs in acute renal ischemia. Indeed, FVB/NJ mice that were subjected to acute renal ischemia showed a transient surge in UA level in the peripheral blood. Single-dose treatment with UA, as well as acute hyperuricemia induced by the inhibition of uricase, caused a robust mobilization of EPCs, whereas administration of adenosine or inosine seemed to lack this effect. Moreover, pretreatment of mice with a single dose of UA afforded significant renoprotection against ischemic injury. In animals with chronic hyperuricemia (induced by continuous 2-wk treatment with a uricase inhibitor oxonic acid), EPC mobilization was blunted and renoprotective effects were absent. In conclusion, acute elevation of UA acts as "physiologic," fast-acting endogenous mediator of EPC mobilization and renoprotection, consistent with its novel function in pharmacologic preconditioning. Both of these actions are lacking in mice with chronic hyperuricemia. In summary, a transient surge in UA concentration may serve as a universal herald of tissue injury to accelerate the recruitment of EPCs

Renal cell carcinoma: Resistance to therapy, role of apoptosis, and the prognostic and therapeutic target potential of TRAF proteins

Renal cell carcinoma (RCC) is the commonest of the renal neoplasms. Although surgery and cryoablation are successful curative treatments for localized RCC, most patients are diagnosed with advanced or metastatic RCC, which has a poor prognosis. RCC are a heterogeneous set of cancers that have traditionally been classified and staged using cellular characteristics, size, local extension and distant metastases. Current staging systems provide good prognostic information, but it is very likely that the identification of new more accurate and predictive prognostic markers, not currently included in traditional staging systems, will improve the outcome for RCC patients. For this reason, increased knowledge of the underlying molecular characteristics of RCC development and progression is necessary. In most cancers, but especially RCC, deregulated control of apoptosis contributes to cancer growth by aberrantly extending cell viability and facilitating resistance to cancer therapies. Here we present the hypothesis that select members of the tumor necrosis factor (TNF) superfamily, the TNF receptor-associated factors (TRAFs), have a role in RCC apoptosis and may have prognostic significance for RCC. Candidate biomarkers for RCC are few, and the TRAFs may be important inclusions in panels of biomarkers for RCC. TRAFs may also be potential molecular targets for new therapies, either through their ability to promote apoptosis in the cancers themselves, or through their ability to modulate the immune defence against cancer progression. Some support data are presented here for our hypothesis. However, these novel concepts need further careful analysis to allow clinicians and oncologists any assistance for earlier detection of RCC and for characterizing patients with RCC for individualised targeted therapy

DETECTION OF NITRIC OXIDE REDUCTION DURING ISCHAEMIA-REPERFUSION BY EPR SPECTROSCOPY

Introduction: Acute renal failure is a common consequence of sepisis due to concurrent renal ischaemia. The role of nitric oxide (NO) in endotoxaemia and in ischaemic injury in the kidney is not well defined. Material and Methods: In this study we have used an animal model of sepsis induced by injection of bacterial lipopolysaccharide (LPS) in the rat and measured renal nitric oxide by X-band electron paramagnetic resonance (EPR) spectroscopy using the spin trap Fe2+-N-methyl-D-glucamine dithiocarbamate [Fe(MGD)2] given by intravenous injection 6 minutes before sacrifice. Results: The characteristic EPR spectrum of [Fe(NO)(MGD)2] was observed in kidneys of rats treated with LPS for 5h. Rat kidneys subjected to 20 min ischaemia and 5 min reperfusion had lower concentrations of [Fe(NO)(MGD)2] (1.0 ± 0.6 (M) compared to the contralateral nonischaemic kidneys (1.5 ± 0.9 (M, P<0.05). Conclusion: This study shows reduced levels of NO after renal ischaemia in vivo

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure

Administration of human recombinant erythropoietin ( EPO) at time of acute ischemic renal injury ( IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa ( DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats ( N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation ( T0), or post-treated ( 6 h after the onset of reperfusion, T6) with EPO ( 5000 IU/kg), DPO ( 25 mu g/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.08 +/- 0.03mmol/l vs EPO-IRI 0.04 +/- 0.01mmol/l, P = 0.01). Delayed administration of DPO or EPO ( T6) also significantly abrogated subsequent renal dysfunction ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.06 +/- 0.01mmol/l vs EPO-IRI 0.03 +/- 0.03mmol/l, P = 0.01). There was also significantly decreased tissue injury ( apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult

Acinar cell apoptosis and the origin of tubular complexes in caerulein-induced pancreatitis

The interrelationship between acinar cell apoptosis and tubular complex formation was examined in caerulein-induced pancreatitis using histology, immunohistochemistry, electron microscopy and DNA gel electrophoresis. Rats were given 8 hourly subcutaneous injections of caerulein, 24μg/kg, for up to 2 days. Morphologically and biochemically typical apoptosis affected 4.6 and 8.9% of acinar cells at 1 and 2 days, respectively, resulting in removal of most acinar cells by 2 days. Consequently, pancreatic ducts, the lining cells expressing bcl-2 and therefore resistant to apoptosis, became much more closely approximated to form the basis of tubular complexes; small numbers of immunohistochemically discrete acinar cells in their lining were either pre-apoptotic resistant to it or newly formed. Proliferation of duct-like lining cells was associated with apoptosis, an increase in islet cells and acinar cell regeneration. There was evidence of duct to acinar cell differentiation but the main increase in acinar cell numbers appeared to derive from proliferation of newly formed acinar cells