Nephrotoxicity is one of the most important side effects and therapeutical limitations of aminoglycoside antibiotics, especially gentamicin. Despite rigorous patient monitoring, nephrotoxicity appears in 10-25% of therapeutic courses. Traditionally, aminoglycoside nephrotoxicity has been considered to result mainly from tubular damage. Both lethal and sub-lethal alterations in tubular cells handicap reabsorption and, in severe cases, may lead to a significant tubular obstruction. However, a reduced glomerular filtration is necessary to explain the symptoms of the disease. Reduced filtration is not solely the result of tubular obstruction and tubular malfunction, resulting in tubuloglomerular feedback activation; renal vasoconstriction and mesangial contraction are also crucial to fully explain aminoglycoside nephrotoxicity. This review critically presents an integrative view on the interactions of tubular, glomerular, and vascular effects of gentamicin, in the context of the most recent information available. Moreover, it discusses therapeutic perspectives for prevention of aminoglycoside nephrotoxicity derived from the pathophysiological knowledge.

Co-treatment with quercetin partially prevented all the renal effects of cisplatin, whereas it did not impair its anti-tumour activity. In conclusion, in a model of tumour-bearing rats, quercetin prevents the nephrotoxic effect of cisplatin without affecting its anti-tumour activity.

The transcription factor NF-B is overexpressed or constitutively activated in many cancer cells, where it induces expression of antiapoptotic genes correlating with resistance to anticancer therapies. Small molecules that inhibit the NF-B signaling pathway could therefore be used to induce apoptosis in NF-B-overexpressing tumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited the activation of NF-B-dependent transcriptional activity in different tumor cell lines. MX781 was able to completely inhibit tumor necrosis factor alpha-mediated activation of IB kinase (IKK), the upstream regulator of NF-B. Inhibition of IKK activity resulted from direct binding of MX781 to the kinase, as demonstrated by in vitro inhibition studies. Two other molecules, MX3350-1 and CD2325, which are retinoic acid receptor gamma-selective agonists, were capable of inhibiting IKK in vitro, although they exerted variable inhibition of IKK and NF-B activities in intact cells in a cell type-specific manner. However, N-(4-hydroxyphenyl)-retinamide, another apoptosis-inducing retinoid, and retinoic acid as well as other nonapoptotic retinoids did not inhibit IKK. Inhibition of IKK by the retinoid-related compounds and other small molecules correlated with reduced cell proliferation and increased apoptosis. Reduced cell viability was also observed after overexpression of an IKK␤ kinase-dead mutant or the IB␣ superrepressor. The induction of apoptosis by the retinoid-related molecules that inhibited IKK was dependent on caspase activity but independent of the retinoid receptors. Thus, the presence of an excess of retinoic acid or a retinoid antagonist did not prevent the inhibition of IKK activation by MX781 and CD2325, indicating a retinoid receptor-independent mechanism of action.

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Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X L also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VADfmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. Nephrotoxicity is the most serious and common adverse effect of deferasirox and may present as an acute or chronic kidney disease. However, scarce data are available on the molecular mechanisms of nephrotoxicity. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. Deferasirox induced dose-dependent tubular cell death and AnexxinV/7AAD staining showed features of apoptosis and necrosis. However, despite inhibiting caspase-3 activation, the pan-caspase inhibitor zVAD-fmk failed to prevent deferasirox-induced cell death. Moreover, zVAD increased deferasirox-induced cell death, a feature sometimes found in necroptosis. Electron microscopy identified mitochondrial injury and features of necrosis. However, neither necrostatin-1 nor RIP3 knockdown prevented deferasirox-induced cell death. Deferasirox caused BclxL depletion and BclxL overexpression was protective. Preventing iron depletion protected from BclxL downregulation and deferasirox cytotoxicity. In conclusion, deferasirox promoted iron depletion-dependent cell death characterized by BclxL downregulation. BclxL overexpression was protective, suggesting a role for BclxL downregulation in iron depletion-induced cell death. This information may be used to develop novel nephroprotective strategies. Furthermore, it supports the concept that monitoring kidney tissue iron depletion may decrease the risk of deferasirox nephrotoxicity.

Retinoids mediate numerous biological responses through the transcriptional activation of nuclear retinoid receptors. Due to their antiproliferative activity, retinoids have shown promise as anticancer agents. Synthetic analogs have been described that selectively activate one subset of the retinoid receptors or inhibit their transcriptional activity. Some of these compounds exhibit strong anticancer activity, which is associated with their ability to induce apoptosis. Here we describe that the retinoid antagonist MX781 causes a substantial increase of clusterin mRNA and protein levels in prostate carcinoma cells. In contrast, retinoic acid and other synthetic agonists and antagonists show no effect on clusterin mRNA/protein levels. Induction of clusterin mRNA is associated with transcriptional activation of the clusterin promoter, which requires the proximal ؊218-bp region containing binding sites for heat shock factor (HSF)-1, activator protein (AP)-2, and AP-1 transcription factors. MX781 slightly induces AP-1 DNA binding activity, and mutation of the AP-1 site differentially affects the activation of the clusterin promoter in a cell type-specific manner. In contrast, a robust increase of HSF-1 DNA binding activity is observed in all cancer cell lines examined, and mutation of the heat shock element site in the clusterin promoter completely abolishes MX781-induced transcriptional activation in PC3 and DU145 cells. Other agonist retinoid-related molecules also induce AP-1 activity, but not HSF-1, and elicit no effect on clusterin expression levels. These data point to HSF-1 as an important factor regulating clusterin expression in response to MX781, although AP-1 activity may also participate in a cell type-specific manner.

Acute renal failure induced by renal ischemia or drugs continues to be a relevant clinical problem. Li et al. have demonstrated that proximal tubule-restricted peroxisome proliferator-activated receptor-alpha (PPARalpha) expression in transgenic mice reduced cisplatin- and ischemia/reperfusion-induced acute renal injury. Their article suggests a role for the maintenance of free fatty acid oxidation in the proximal tubule as a mechanism of nephroprotection, as well as a potential clinical utility of PPARalpha activators in the prevention of acute renal failure.