guanosine-triphosphate and Acute-Kidney-Injury

Apoptosis is increasingly recognized as a major mode of cell demise after ischemic injury to the kidney. The mediators of apoptotic cell death are many and include changes in intracellular pH, calcium, free radicals, ceramide, and adenosine triphosphate (ATP) depletion. Recently, we identified guanosine triphosphate (GTP) depletion as an independent trigger for apoptotic death after chemical anoxia in vitro. We further demonstrated that GTP salvage with guanosine inhibits tubular cell apoptosis after ischemic injury in vivo. This inhibition of apoptosis was accompanied by a significant protective effect on renal function. We also showed that p53 is the mediator of apoptosis in the setting of GTP depletion and ischemic injury. Indeed, salvage of GTP with guanosine prevented the ischemia-induced increase in p53 protein. Further, pifithrin-alpha, a potent and specific inhibitor of p53, inhibited apoptosis and protected renal function with a profile similar to that seen with guanosine. Finally, the protective effects of pifithrin-alpha involved both down-regulation of the transcriptional activation of Bax and a direct inhibition of p53 translocation to mitochondria. We propose that GTP depletion and activation of p53 are major inducers of apoptotic cell death after ischemic renal injury. In this setting, guanosine and pifithrin-alpha are potent inhibitors of apoptosis and are thus potentially useful in preventing and ameliorating functional injury to the ischemic kidney.

Topics: Acute Kidney Injury; Animals; Apoptosis; Guanosine Triphosphate; Humans; Ischemia; Tumor Suppressor Protein p53

Renal tubular cells die by apoptosis as well as necrosis in experimental models of ischemic and toxic acute renal failure as well as in humans with acute tubular necrosis. It is not yet possible, however, to determine the relative contribution of these two forms of cell death to loss of renal tubular cells in acute tubular necrosis. The beneficial effect of administering growth factors to animals with acute tubular necrosis is probably related to the potent antiapoptotic (survival) effects of growth factors as well as to their proliferative effects. Rapamycin inhibits both of these effects of growth factors and delays the recovery of renal function after acute tubular necrosis by inhibiting renal tubular cell regeneration and by increasing renal tubular cell loss by apoptosis. The administration of caspase inhibitors ameliorates ischemia-reperfusion injury in multiple organs including the kidney. However, the extent to which this protective effect of caspase inhibition is caused by reduced intrarenal inflammation, or by amelioration of renal tubular cell loss due to apoptosis, remains uncertain. In addition to caspase inhibition, the apoptotic pathway offers many potential targets for therapeutic interventions to prevent renal tubular cell apoptosis.

Topics: Acute Kidney Injury; Apoptosis; Caspase Inhibitors; Cell Adhesion; Cisplatin; Growth Substances; Guanosine Triphosphate; Humans; Ischemia; Kidney Tubules; Necrosis; Sirolimus

Biochemical changes in the blood following induction of renal failure by glycerol or mercuric chloride have been studied in 16 rats. Plasma creatinine, urea and Pi levels indicated that renal impairment followed the same time course in both renal failure models, with the severest effects on day 3 and returning to normal by day 7. Erythrocyte ATP and guanine triphosphate (GTP) levels were significantly elevated above contorl values on day 1 and remained elevated in both models. ATP/ADP and GTP/GDP ratios also increased in both models. In renal failure the increased purine 'salvage' in the erythrocyte may be attributed to accumulation of purine metabolites in the serum associated with increased P-ribose-PP levels due to elevated cellular Pi. Nucleotide changes in both these models are analogous to those found in chronic renal failure in man.

Topics: Acute Kidney Injury; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Chlorides; Creatinine; Disease Models, Animal; Erythrocytes; Female; Glycerol; Guanosine Diphosphate; Guanosine Triphosphate; Mercury; Nucleotides; Phosphates; Rats; Urea