Francisco J. López-Hernández

New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view

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.

Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects.

Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-β induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-β has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-β participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD.

An Integrative Overview on the Mechanisms Underlying the Renal Tubular Cytotoxicity of Gentamicin

Gentamicin is an aminoglycoside antibiotic widely used against infections by Gram-negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy. Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by megalin and cubulin, which transports proteins and organic cations inside the cells. Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of gentamicin, such as reduced renal blood flow and inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death.

An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity.

Cisplatin is among the most effective chemotherapeutic agents against solid tumors. Nephrotoxicity is the most common side effect of cisplatin chemotherapy, which limits the clinical use of cisplatin and seriously worsens the quality of life of cancer patients resulting in dosage reduction and discontinuation of treatment. Cisplatin involves a complex multifactorial process, as it has direct toxic effect on cells of the renal tubules, vasculature and glomeruli, and causes alterations in renal blood flow and glomerular filtration rate. Indirectly, cisplatin also induces inflammation of the renal interstitium, which contributes to the acute damage and may lead to chronic interstitial fibrosis, indicative of irreversible renal damage. This review presents an integrative view of the pathophysiological effects of cisplatin on tubular, vascular, glomerular, and interstitial function and the interplay among these actions. Moreover, it reviewed human clinical trials of the last ten years in order to evaluate the incidence and severity of the renal injury induced by cisplatin at the doses and therapeutic guidelines used in the clinical practice.

An integrative view on the role of TGF-β in the progressive tubular deletion associated with chronic kidney disease

Transforming growth factor-beta (TGF-beta) is a cytokine known to participate in several processes related to the development of chronic kidney disease (CKD), including tubular degeneration. This is thought to occur mainly through apoptosis and epithelial-to-mesenchymal transition (EMT) of tubule epithelial cells, which give rise to a reduction of the tubular compartment and a scarring-like, fibrotic healing process of the interstitial compartment. In vivo blockade of TGF-beta action has been shown to reduce CKD-associated tubular damage. However, a direct action of TGF-beta on tubule cells is controversial as the underlying mechanism. On the one hand, TGF-beta is known to induce EMT of tubular cells, although its incidence in vivo can hardly explain the extent of the damage. On the other hand, a few publications have reported that TGF-beta induces a mild degree of apoptosis in cultured tubular cells. This most likely reflects the consequence of the cell-cycle arrest rather than a direct pro-apoptotic effect of TGF-beta. The implications of these observations are analyzed in the pathological context, where normal tubular cells do not normally proliferate, but they might divide for repair purposes. Furthermore, renal fibrosis, a TGF-beta-mediated event, is integrated as a potential, indirect effect contributing to tubule deletion.

Subcellular targets of cisplatin cytotoxicity: an integrated view.

Cisplatin is a chemotherapeutic drug widely used against a variety of cancers. Its clinical utility is severely limited by its toxicity, which mainly affects, but is not limited to, the inner ear and renal tubules. Cisplatin toxicity is determined by target tissue and cell accumulation, subcellular handling and trafficking through diverse subcellular structures, and interaction with macromolecules. Cisplatin accumulates and stresses different organelles from which delay signaling is activated, including mitochondria, lysosomes, the endoplasmic reticulum, the nucleus, the cell membrane and cytoskeleton, and can also be found in the cytosol. This article critically summarizes the available information in order to establish the connection among its known subcellular effects in a hierarchical and integrative framework. Cisplatin causes different types of cell death in a concentration-dependent manner. Knowledge of the events and signaling leading to the different phenotypes is also intertwined within the model, within the scope of the potential utility of this information in the improvement of the pharmacotoxicological profile of this drug. Perspectives for the key aspects that need to be addressed by future investigation are also outlined.

Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity

BACKGROUND Nephrotoxicity is the major limitation for the clinical use of cisplatin as an anti-tumoural drug. Our aim was to investigate the protective effect of quercetin on cisplatin nephrotoxicity in a rat tumour model in vivo and to examine the mechanisms of renal protection. METHODS Breast adenocarcinoma (13762 Mat B-III) cells were inoculated subcutaneously in male Fischer rats and 7 days later, the rats were administered daily with quercetin [50 mg/kg/day, intraperitoneally (i.p.)] or vehicle. Four days after that, the rats were given a single dose of cisplatin (4 mg/kg, i.p.) or vehicle. Tumour growth and renal function were monitored throughout the experiment. Two or 6 days after cisplatin administration, the rats were killed and the kidneys and tumours were removed to examine renal function and toxicity markers in both tissues. RESULTS In the kidney, cisplatin treatment induced: (i) a decrease in renal blood flow and glomerular filtration rate, (ii) tubular necrosis/apoptosis, (iii) increased lipid peroxidation and decreased endogenous antioxidant systems, (iv) increased expression of inflammation markers and (v) increased activity of the apoptosis executioner caspase-3. Cisplatin effectively reduced tumour size and weight. CONCLUSIONS 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.

Nephrotoxicity of Uranium: Pathophysiological, Diagnostic and Therapeutic Perspectives

As in the case of other heavy metals, a considerable body of evidence suggests that overexposure to uranium may cause pathological alterations to the kidneys in both humans and animals. In the present work, our aim was to analyze the available data from a critical perspective that should provide a view of the real danger of the nephrotoxicity of this metal for human beings. A further aim was to elaborate a comparative compilation of the renal pathophysiological data obtained in humans and experimental animals with a view to gaining more insight into our knowledge of the mechanisms of action and renal damage. Finally, we address the existing perspectives for the improvement of diagnostic methods and the treatment of intoxications by uranium, performing an integrated analysis of all these aspects.

Inhibition of IκB Kinase by a New Class of Retinoid-Related Anticancer Agents That Induce Apoptosis

ABSTRACT The transcription factor NF-κB 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-κB signaling pathway could therefore be used to induce apoptosis in NF-κB-overexpressing tumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited the activation of NF-κB-dependent transcriptional activity in different tumor cell lines. MX781 was able to completely inhibit tumor necrosis factor alpha-mediated activation of IκB kinase (IKK), the upstream regulator of NF-κB. 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-κB 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 IKKβ kinase-dead mutant or the IκBα 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.

Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives

Retinoid derivatives have been of special interest in cancer research because of their antiproliferative and differentiation-inducing activities in premalignant and malignant cells. Some retinoids are clinically effective in cancer therapy and prevention, and all-trans-retinoic acid is being used for the treatment of acute promyelocytic leukemia. Unfortunately, classical retinoids are not effective against most advanced solid tumors and cause undesirable side effects, which have limited the full development of retinoids as chemopreventive and chemotherapeutic drugs. The recent identification of selective retinoid derivatives capable of inducing apoptosis and their combination with other anticancer therapies promises a more effective and less toxic manner to the successful use of retinoids in cancer therapy.