The kidney consists of numerous cell types organized into the nephron, which is the basic functional unit of the kidney. Any stimuli that induce loss of these cells can induce kidney damage and renal failure. The cause of renal failure can be intrinsic or extrinsic. Extrinsic causes include cardiovascular disease, obesity, diabetes, sepsis, and lung and liver failure. Intrinsic causes include glomerular nephritis, polycystic kidney disease, renal fibrosis, tubular cell death, and stones. The kidney plays a prominent role in mediating the toxicity of numerous drugs, environmental pollutants and natural substances. Drugs known to be nephrotoxic include several cancer therapeutics, drugs of abuse, antibiotics, and radiocontrast agents. Environmental pollutants known to target the kidney include cadmium, mercury, arsenic, lead, trichloroethylene, bromate, brominated-flame retardants, diglycolic acid, and ethylene glycol. Natural nephrotoxicants include aristolochic acids and mycotoxins such as ochratoxin, fumonisin B1, and citrinin. There are several common characteristics between mechanisms of renal failure induced by nephrotoxicants and extrinsic causes. This common ground exists primarily due to similarities in the molecular mechanisms mediating renal cell death. This review summarizes the current state of the field of nephrotoxicity. It emphasizes integrating our understanding of nephrotoxicity with pathological-induced renal failure. Such approaches are needed to address major questions in the field, which include the diagnosis, prognosis and treatment of both acute and chronic renal failure, and the progression of acute kidney injury to chronic kidney disease.

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Bromate (BrO À 3) is a water disinfection byproduct (DBP) previously shown to induce nephrotoxicity in vitro and in vivo. We recently showed that inhibitors of DNA methyltransferase 5-aza-2 0-deoxycytidine (5-Aza) and histone deacetylase trichostatin A (TSA) increased BrO À 3 nephrotoxicity whereas altering the expression of the cyclin-dependent kinase inhibitor p21. Human embryonic kidney cells (HEK293) and normal rat kidney (NRK) cells were sub-chronically exposed to BrO À 3 or epigenetic inhibitors for 18 days, followed by 9 days of withdrawal. DNA methylation was studied using a modification of bisulfite amplicon sequencing called targeted gene bisulfite sequencing. Basal promoter methylation in the human p21 promoter region was substantially lower than that of the rat DNA. Furthermore, 5-Aza decreased DNA methylation in HEK293 cells at the sis-inducible element at 3 distinct CpG sites located at 691, 855, and 895 bp upstream of transcription start site (TSS). 5-Aza also decreased methylation at the rat p21 promoter about 250 bp upstream of the p21 TSS. In contrast, sub-chronic BrO À 3 exposure failed to alter methylation in human or rat renal cells. BrO À 3 exposure altered histone acetylation in NRK cells at the p21 TSS, but not in HEK293 cells. Interestingly, changes in DNA methylation induced by 5-Aza persisted after its removal; however, TSA-and BrO À 3-induced histone hyperacetylation returned to basal levels after 3 days of withdrawal. These data demonstrate novel sites within the p21 gene that are epigenetically regulated and further show that significant differences exist in the epigenetic landscape between rat and human p21, especially with regards to toxicant-induced changes in histone acetylation.

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Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.