Abstract
Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFβ pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 μM) as compared with those in controls. Zoledronate treatments in cells (50 μM) and mice (3 mg/kg) increased TGFβ/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid β-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.
Highlights
Zoledronate is a highly potent nitrogen-containing bisphosphonate that is commonly used to treat osteoporosis, hypercalcemia of malignancy and osteolytic bone metastases (Munier et al 2005; Perazella and Markowitz 2008; Roelofs et al 2006)
Despite the clinical importance of zoledronate in several therapeutic areas, numerous cases of zoledronate-associated nephrotoxicity have been reported, which are shown to lead to renal failure, acute tubular necrosis and renal fibrosis characterized by tubular cell degeneration, loss of brush border, and apoptosis, when given intravenously (Chang et al 2003; Markowitz et al 2003; McKay et al 2014; Munier et al 2005; Ott 2012; Papapetrou 2009; Perazella and Markowitz 2008; Verhulst et al 2015)
The graph shows the negative log p values for the enrichment of the specific pathways. d Relative protein levels related to TGFβ1 receptor agonist (TGFβ) and inflammation. e Relative protein levels related to fibrosis and kidney injury. f Relative protein levels related to lipid and fatty acid (FA) metabolism
Summary
Zoledronate is a highly potent nitrogen-containing bisphosphonate that is commonly used to treat osteoporosis, hypercalcemia of malignancy and osteolytic bone metastases (Munier et al 2005; Perazella and Markowitz 2008; Roelofs et al 2006). It inhibits farnesyl diphosphate synthase (FPPS), an enzyme in the mevalonate pathway for cholesterol biosynthesis, and this inhibition reduces post-translational lipid modification (prenylation) of small GTPases (Roelofs et al 2006). The mechanism underlying zoledronate-induced renal toxicity remains unclear
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