Govind Darshana, Meamardoost Saber, Yacoub Rabi, Gunawan Rudiyanto, Tomaszewski John E, Sarder Pinaki
Department of Pathology and Anatomical Sciences, University at Buffalo, Buffalo, NY.
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY.
Proc SPIE Int Soc Opt Eng. 2022 Feb-Mar;12039. doi: 10.1117/12.2614495. Epub 2022 Apr 4.
Podocyte injury plays a crucial role in the progression of diabetic kidney disease (DKD). Injured podocytes demonstrate variations in nuclear shape and chromatin distribution. These morphometric changes have not yet been quantified in podocytes. Furthermore, the molecular mechanisms underlying these variations are poorly understood. Recent advances in omics have shed new lights into the biological mechanisms behind podocyte injury. However, there currently exists no study analyzing the biological mechanisms underlying podocyte morphometric variations during DKD. First, to study the importance of nuclear morphometrics, we performed morphometric quantification of podocyte nuclei from whole slide images of renal tissue sections obtained from murine models of DKD. Our results indicated that podocyte nuclear textural features demonstrate statistically significant difference in diabetic podocytes when compared to control. Additionally, the morphometric features demonstrated the existence of multiple subpopulations of podocytes suggesting a potential cause for their varying response to injury. Second, to study the underlying pathophysiology, we employed single cell RNA sequencing data from the murine models. Our results again indicated five subpopulations of podocytes in control and diabetic mouse models, validating the morphometrics-based results. Additionally, gene set enrichment analysis revealed epithelial to mesenchymal transition and apoptotic pathways in a subgroup of podocytes exclusive to diabetic mice, suggesting the molecular mechanism behind injury. Lastly, our results highlighted two distinct lineages of podocytes in control and diabetic cases suggesting a phenotypical change in podocytes during DKD. These results suggest that textural variations in podocyte nuclei may be key to understanding the pathophysiology behind podocyte injury.
足细胞损伤在糖尿病肾病（DKD）的进展中起关键作用。受损的足细胞表现出核形状和染色质分布的变化。这些形态计量学变化尚未在足细胞中进行量化。此外，这些变化背后的分子机制也知之甚少。组学的最新进展为足细胞损伤背后的生物学机制提供了新的线索。然而，目前尚无研究分析DKD期间足细胞形态计量学变化背后的生物学机制。首先，为了研究核形态计量学的重要性，我们对从DKD小鼠模型获得的肾组织切片的全玻片图像中的足细胞核进行了形态计量学量化。我们的结果表明，与对照组相比，糖尿病足细胞的足细胞核纹理特征显示出统计学上的显著差异。此外，形态计量学特征表明存在多个足细胞亚群，这表明它们对损伤反应不同的潜在原因。其次，为了研究潜在的病理生理学，我们使用了来自小鼠模型的单细胞RNA测序数据。我们的结果再次表明，在对照和糖尿病小鼠模型中有五个足细胞亚群，验证了基于形态计量学的结果。此外，基因集富集分析揭示了糖尿病小鼠特有的一个足细胞亚群中的上皮-间质转化和凋亡途径，这表明了损伤背后的分子机制。最后，我们的结果突出了对照和糖尿病病例中两种不同的足细胞谱系，表明DKD期间足细胞的表型变化。这些结果表明，足细胞核的纹理变化可能是理解足细胞损伤背后病理生理学的关键。
