Limited understanding of species differences in kidney transporters is a critical knowledge gap for prediction of drug-induced acute kidney injury, drug interaction, and pharmacokinetics in humans. Here, we report protein abundance data of nineteen transporters in the kidney cortex across five species (human, monkey, dog, rat, and mouse). In general, the abundance of all the 19 membrane transporters was higher in preclinical species as compared to human except for MDR1, OCT3 and OCTN1. In nonhuman primate, the total abundance of 12 transporters for which absolute data were available, was 2.1-fold higher (p value = 0.025) relative to human but the % distribution of these transporters was identical in both species. MRP4, OCTN2, OAT2, Na+K+ATPase, MRP3, SGLT2, OAT1, MRP1, MDR1, OCT2 were expressed differently with cross-species variability of 8.2, 7.4, 6.1, 5.9, 5.4, 5.2, 4.1, 3.3 and 2.8-fold, respectively. Sex differences were only significant in rodents and dog. High protein-protein correlation was observed in OAT1 versus MRP2/MRP4 as well as OCT2 versus MATE1 in human and monkey. The cross-species and sex-dependent protein abundance data are important for animal to human scaling of drug clearance as well as for mechanistic understanding of kidney physiology and derisking of kidney toxicity for new therapeutic candidates in drug development. SIGNIFICANCE STATEMENT Prediction of drug-induced acute kidney injury, drug interaction, and pharmacokinetics in humans from animal data requires understanding of cross-species abundance of drug transporters in drug disposition relevant tissues, e.g., kidney, liver and intestine. We quantified protein abundance data of nineteen transporters in the kidney cortex across human, monkey, dog, rat, and mouse. Significant quantitative differences were observed in transporter abundance across species. Further, few transporters were only detected in specific species, e.g., OCT3 in human and BCRP in rodents. Moreover, several proteins (OAT1 versus MRP2/MRP4 and OCT2 versus MATE1) showed significant protein-protein correlations. These quantitative protein abundance data are important for mechanistic understanding of kidney toxicity and prediction of human renal drug clearance from animal data.

Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphingolipid signaling in melanoma. We found that AC expression is markedly elevated in normal human melanocytes and proliferative melanoma cell lines, compared with other skin cells (keratinocytes and fibroblasts) and non-melanoma cancer cells. High AC expression was also observed in biopsies from human subjects with Stage II melanoma. Immunofluorescence studies revealed that the subcellular localization of AC differs between melanocytes (where it is found in both cytosol and nucleus) and melanoma cells (where it is primarily localized to cytosol). In addition to having high AC levels, melanoma cells generate lower amounts of ceramides than normal melanocytes do. This down-regulation in ceramide production appears to result from suppression of the de novo biosynthesis pathway. To test whether AC might contribute to melanoma cell proliferation, we blocked AC activity using a new potent (IC₅₀ = 12 nm) and stable inhibitor. AC inhibition increased cellular ceramide levels, decreased sphingosine 1-phosphate levels, and acted synergistically with several, albeit not all, antitumoral agents. The results suggest that AC-controlled sphingolipid metabolism may play an important role in the control of melanoma proliferation.

Huntington’s disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.