Genomic-Derived Markers for Early Detection of Calcineurin Inhibitor Immunosuppressant-Mediated Nephrotoxicity

Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Toxicological Sciences (Impact Factor: 3.85). 08/2011; 124(1):23-34. DOI: 10.1093/toxsci/kfr217
Source: PubMed


Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.6 or 6 mg/kg/day), or rapamycin (1 or 10 mg/kg/day) for 1, 7, 14, or 28 days. A significant increase in blood urea nitrogen was observed in animals treated with CsA (high) or FK506 (high) for 14 and 28 days. Histopathological examination revealed tubular basophilia and mineralization in animals given CsA (high) or FK506 (low and high). We identified a group of genes whose expression in rat kidney is correlated with CI-induced kidney injury. Among these genes are two genes, Slc12a3 and kidney-specific Wnk1 (KS-Wnk1), that are known to be involved in sodium transport in the distal nephrons and could potentially be involved in the mechanism of CI-induced nephrotoxicity. The downregulation of NCC (the Na-Cl cotransporter coded by Slc12a3) in rat kidney following CI treatment was confirmed by immunohistochemical staining, and the downregulation of KS-Wnk1 was confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR). We hypothesize that decreased expression of Slc12a3 and KS-Wnk1 could alter the sodium chloride reabsorption in the distal tubules and contribute to the prolonged activation of the renin-angiotensin system, a demonstrated contributor to the development of CI-induced nephrotoxicity in both animal models and clinical settings. Therefore, if validated as biomarkers in humans, SLC12A3 and KS-WNK1 could potentially be useful in the early detection and reduction of CI-related nephrotoxicity in immunosuppressed transplant patients when monitoring the health of kidney xenographs in clinical practice.

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    • "According to that reported in literature [12],to verify that in our cellular system CsA increases the NGF levels via NFATc1 inhibition, HK-2 cells treated with CsA for 48 h, were pre-treated with phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (Io) to induce NFATc1 activation. As expected, the exposure to PMA plus Io, increased NFATc1 levels of 50 ± 15.0 %; interestingly, in HK-2 cells treated with NFATc1 activators, the exposure to CsA did not increased NGF protein levels, indeed we observed that upon PMA+Io+CsA NGF expression was significantly decreased (-80 ± 4.50 %), emphasizing that CsA increases NGF levels via NFATc1 (Figure 1D). "
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    Preview · Article · Dec 2011 · Nephrology Dialysis Transplantation
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