Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell Metab. 2021 May 4;33(5):1042-1061.e7. doi: 10.1016/j.cmet.2021.04.004.
Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.
肾小管间质异常可预测糖尿病肾病 (DKD) 的进展，针对这些异常进行治疗可能是一种有效的预防手段。人糖尿病早期，近端肾小管 (PT) 表达的肾损伤分子 (KIM)-1 及其血液和尿液水平升高，可预测疾病进展速度。本研究报告称，KIM-1 介导 PT 摄取与棕榈酸 (PA) 结合的白蛋白，导致 DNA 损伤、PT 细胞周期停滞、间质炎症和纤维化以及继发性肾小球硬化，从而加重肾小管损伤。在高脂肪喂养的链脲佐菌素诱导的 DKD 小鼠模型中，通过基因敲除 KIM-1 粘蛋白结构域可减轻这种损伤。我们还发现 TW-37 是一种抑制 KIM-1 介导的 PA-白蛋白摄取的小分子抑制剂，并在小鼠肾脏损伤模型中证明，它可改善肾脏炎症和纤维化。综上所述，这些发现支持 KIM-1 作为 DKD 的一个新的治疗靶点。
