SIRT6 Protects renal tubular epithelial cells from hyperoxaluria

Hyperoxaluria disrupts the balance between cellular damage and repair within renal tubular epithelial cells contributing to the development of crystal nephropathy. SIRT6 repairs damage in many diseases. How about in kidney stones? In our present investigation, we confirmed that SIRT6 was abundantly located in normal renal tubular epithelial cells. However, its expression was significantly reduced in cells of patients with kidney stones. Meanwhile the level of DNA damage was markedly elevated. A negative correlation was found. Functionally, the agonist or the overexpression of SIRT6 could effectively alleviate the cells injury and suppress the crystals deposition in kidney. In addition, the inhibitor of SIRT6 reversed these beneficial effects and exacerbated the formation of crystal nephropathy. Furthermore, we discovered that SIRT6 exerted its protective function by promoting DNA damage repair with MacroH2A1 and PARP1. However, in hyperoxaluria, SIRT6 underwent ubiquitination and bound to heat shock protein 70, then extensively degraded via the autophagy lysosome pathway. Blocking the degradation protected cells from hyperoxaluria. In summary, our findings confirm that modulating SIRT6 levels can re-establish the intrinsic balance between injury and repair in renal tubular epithelial cells under hyperoxaluria. These results hold great promise in providing a novel therapeutic target for the prevention and treatment of kidney stones.