Functional TauT Protects Against Acute Kidney Injury

Nephrotoxicity is common with the use of the chemotherapeutic agent cisplatin, but the cellular mechanisms that modulate the extent of injury are unknown. Cisplatin downregulates expression of the taurine transporter gene (TauT) in LLC-PK1 proximal tubular renal cells, and forced overexpression of TauT protects against cisplatin-induced apoptosis in vitro. Because the S3 segments of proximal tubules are the sites of both cisplatin-induced injury and adaptive regulation of the taurine transporter, we hypothesized that TauT functions as an anti-apoptotic gene and protects renal cells from cisplatin-induced nephrotoxicity in vivo. Here, we studied the regulation of TauT in cisplatin nephrotoxicity in a human embryonic kidney cell line and in LLC-PK1 cells, as well as in TauT transgenic mice. Cisplatin-induced activation of p53 repressed TauT and overexpression of TauT prevented the progression of cisplatin-induced apoptosis and renal dysfunction in TauT transgenic mice. Although cisplatin activated p53 and PUMA (a p53-responsive proapoptotic Bcl-2 family protein) in the kidneys of both wildtype and TauT transgenic mice, only wildtype animals demonstrated acute kidney injury. These data suggest that functional TauT plays a critical role in protecting against cisplatin-induced nephrotoxicity, possibly by attenuating a p53-dependent pathway.Acute kidney injury due to ischemic or toxic renal damage is a common disorder with mortality of approximately 50%.^1,2 As a highly effective chemotherapeutic agent, cisplatin has been used to treat a wide variety of solid tumors.³ However, 25% to 35% of patients experience a significant decline in renal function after the administration of a single dose of cisplatin.⁴ Several mechanisms, including oxidation, inflammation, genotoxic damage, and cell cycle arrest, have been implicated in cisplatin nephrotoxicity.^5–10Elevated levels of the tumor suppressor gene p53 have been found in the kidneys of animal models of acute kidney injury induced by cisplatin administration.¹¹ Jiang et al.¹² have demonstrated that p53 activation is an early signal in cisplatin-induced apoptosis in renal tubular cells. The Varmus group¹³ has found that transgenic mice overexpressing p53 undergo progressive renal failure through a novel mechanism by which p53 appears to alter cellular differentiation, rather than by growth arrest or the direct induction of apoptosis. These findings suggest that altered expression of certain p53 target gene(s) involved in renal development may be responsible for p53-induced progressive renal injury in p53 transgenic mice.Our studies have shown that TauT is negatively regulated by p53 in renal cells.¹⁴ Interestingly, the progressive renal injury seen in p53 transgenic mice is similar to that previously observed in the offspring of taurine-deficient cats, which showed ongoing kidney damage and abnormal renal and retinal development,¹⁵ suggesting that the taurine transporter gene is an important target of p53 during kidney development and renal injury. It is worth noting that cisplatin accumulates in cells from all nephron segments, but is preferentially taken up by the highly susceptible proximal tubule cells within the S3 segment, which is the site for renal adaptive regulation of TauT.^16,17 A recent study showed that taurine was able to attenuate cisplatin-induced nephrotoxicity and protect renal tubular cells from tubular atrophy and apoptosis.¹⁸ Therefore, downregulation of TauT by p53 may play an important role in cisplatin-induced nephrotoxicity.