Renal and non-renal response of ABC and SLC transporters in chronic kidney disease

Introduction: The solute carrier (SLC) and the ATP-binding cassette (ABC) transporter superfamilies play essential roles in the disposition of small molecules (endogenous metabolites, uremic toxins, drugs) in the blood, kidney, liver, intestine, and other organs. In chronic kidney disease (CKD), the loss of renal function is associated with altered function of remote organs. As renal function declines, many molecules accumulate in the plasma. Many studies now support the view that ABC and SLC transporters as well as drug metabolizing enzymes (DMEs) in renal and non-renal tissues are directly or indirectly affected by the presence of various types of uremic toxins, including those derived from the gut microbiome; this can lead to aberrant inter-organ communication. Areas covered: Here, the expression, localization and/or function of various SLC and ABC transporters as well as DMEs in the kidney and other organs are discussed in the context of CKD and systemic pathophysiology. Expert opinion: According to the Remote Sensing and Signaling Theory (RSST), a transporter and DMEcentric network that optimizes local and systemic metabolism maintains homeostasis in the steady state and resets homeostasis following perturbations due to renal dysfunction. The implications of this view for pharmacotherapy of CKD are also discussed.Fil: Torres, Adriana Monica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmaceuticas. Departamento de Ciencias Fisiológicas. Area Farmacología; ArgentinaFil: Dnyanmote, Ankur V.. Dalhousie University Halifax; CanadáFil: Granados, Jeffry C.. University of California at San Diego; Estados UnidosFil: Nigam, Sanjay K.. University of California at San Diego; Estados Unido

Remote Communication through Solute Carriers and ATP Binding Cassette Drug Transporter Pathways: An Update on the Remote Sensing and Signaling Hypothesis

Recent data from knockouts, human disease, and transport studies suggest that solute carrier (SLC) and ATP binding cassette (ABC) multispecific “drug” transporters maintain effective organ and body fluid concentrations of key nutrients, signaling molecules, and antioxidants. These processes involve transcellular movement of solutes across epithelial barriers and fluid compartments (e.g., blood, cerebrospinal fluid, urine, bile) via “matching” or homologous sets of SLC (e.g., SLC21, SLC22, SLC47) and ABC transporters. As described in the “Remote Sensing and Signaling Hypothesis” (Biochem Biophys Res Commun 323:429–436, 2004; Biochem Biophys Res Commun 351:872–876, 2006; J Biol Chem 282:23841–23853, 2007; Nat Clin Pract Nephrol 3:443–448, 2007; Mol Pharmacol 76:481–490, 2009), highly regulated transporter networks with overlapping substrate preferences are involved in sensing and signaling to maintain homeostasis in response to environmental changes (e.g., substrate imbalance and injury). They function in parallel with (and interact with) the endocrine and autonomic systems. Uric acid (urate), carnitine, prostaglandins, conjugated sex steroids, cGMP, odorants, and enterobiome metabolites are discussed here as examples. Xenobiotics hitchhike on endogenous carrier systems, sometimes leading to toxicity and side effects. By regulation of the expression and/or function of various remote organ multispecific transporters after injury, the overall transport capacity of the remote organ to handle endogenous toxins, metabolites, and signaling molecules may change, aiding in recovery. Moreover, these transporters may play a role in communication between organisms. The specific cellular components involved in sensing and altering transporter abundance or functionality depend upon the metabolite in question and probably involve different types of sensors as well as epigenetic regulation

Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats

ABSTRACT There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl 4 (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl 4 bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl 4 hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0 -96 h) of CCl 4 (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and 14 CCl 4 covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl 4 administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl 4 hepatotoxicity is potentiated due to inhibited tissue repair. Several animal models resembling type 2 diabetes either occur spontaneously or can be induced experimentally. Most of the commonly used models of type 2 diabetes are genetic and have the disadvantage of prohibitive costs, unavailability, and failure to represent etiology of human disease. Consumption of high fat diet leads to insulin resistance and is considered to be a major predisposing factor for type 2 diabetes To address this need, we have refined and characterized an existing model based on high fat diet and a single dose of streptozotocin (STZ, 45 mg/kg i.p.). The principle behind the development of type 2 diabetes is simple. High fat diet elicits insulin resistance, and the rats maintain normoglycemia due to compensatory hyperinsulinemia. Administration of STZ (45 mg/kg i.p.) decreases insulin levels, destroying a population of pancreatic ␤-cells such that the insulin-resistant rats are now unable to maintain normal glucose levels and develop hyperglycemia, even though insulin levels in these rats are comparable with normal diet-fed normoglycemic rats. This is exactly what is seen in human diabetes where insulin resistance precedes hyperglycemia, thereby making this model a good representative of human type 2 diabetic (DB) condition. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.058834. ABBREVIATIONS: STZ, streptozotocin; DB, diabetic; NDB, nondiabetic; ND ϩ STZ, normal diet-fed rats injected streptozotocin; TA, thioacetamide; AA, allyl alcohol; SD, Sprague-Dawley; 3 H-T, tritiated thymidine; HFD, high fat diet-fed rats injected citrate buffer; HFD ϩ STZ, high fat diet-fed rats injected streptozotocin; ND, normal diet fed rats injected citrate buffer; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PCNA, proliferating cell nuclear antigen; MES, 2-(N-morpholino)ethanesulfonic acid