Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
Department of Pathology, University of Utah, Salt Lake City, UT, USA.
Nat Commun. 2024 Sep 13;15(1):8038. doi: 10.1038/s41467-024-52306-5.
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease worldwide. While injury to the podocytes, visceral epithelial cells that comprise the glomerular filtration barrier, drives albuminuria, proximal tubule (PT) dysfunction is the critical mediator of DKD progression. Here, we report that the podocyte-specific induction of human KLF6, a zinc-finger binding transcription factor, attenuates podocyte loss, PT dysfunction, and eventual interstitial fibrosis in a male murine model of DKD. Utilizing combination of snRNA-seq, snATAC-seq, and tandem mass spectrometry, we demonstrate that podocyte-specific KLF6 triggers the release of secretory ApoJ to activate calcium/calmodulin dependent protein kinase 1D (CaMK1D) signaling in neighboring PT cells. CaMK1D is enriched in the first segment of the PT, proximal to the podocytes, and is critical to attenuating mitochondrial fission and restoring mitochondrial function under diabetic conditions. Targeting podocyte-PT signaling by enhancing ApoJ-CaMK1D might be a key therapeutic strategy in attenuating the progression of DKD.
糖尿病肾病（DKD）是全球慢性肾脏病的主要病因。虽然足细胞（构成肾小球滤过屏障的内脏上皮细胞）损伤会导致白蛋白尿，但近端肾小管（PT）功能障碍是 DKD 进展的关键介质。在这里，我们报告称，足细胞特异性诱导人 KLF6（一种锌指结合转录因子）可减轻雄性 DKD 小鼠模型中的足细胞丢失、PT 功能障碍和最终的间质纤维化。我们利用 snRNA-seq、snATAC-seq 和串联质谱联用的方法，证明足细胞特异性 KLF6 可触发分泌型 ApoJ 的释放，以激活邻近 PT 细胞中的钙/钙调蛋白依赖性蛋白激酶 1D（CaMK1D）信号。CaMK1D 在 PT 的第一段富集，靠近足细胞，在糖尿病条件下抑制线粒体裂变和恢复线粒体功能至关重要。通过增强 ApoJ-CaMK1D 来靶向足细胞-PT 信号可能是减轻 DKD 进展的关键治疗策略。
