Spatial proteomics of human diabetic kidney disease, from health to class III,Diabetologia

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Spatial proteomics of human diabetic kidney disease, from health to class III
Diabetologia ( IF 8.4 ) Pub Date : 2024-07-22 , DOI: 10.1007/s00125-024-06210-8
Ayano Kondo ₁ , Monee McGrady ₁ , Dhiraj Nallapothula ₂ , Hira Ali ₁ , Alexandro E Trevino ₁ , Amy Lam ₁ , Ryan Preska ₁ , H Blaize D'Angio ₁ , Zhenqin Wu ₁ , Lauren N Lopez ₂ , Harshanna K Badhesha ₂ , Chenoa R Vargas ₂ , Achyuta Ramesh ₃ , Nasim Wiegley ₂ , Seung Seok Han ₄ , Marc Dall'Era ₅ , Kuang-Yu Jen ₆ , Aaron T Mayer ₁ , Maryam Afkarian ₂

Affiliation

Aims/hypothesis

Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease in the USA and worldwide. Animal models have taught us much about DKD mechanisms, but translation of this knowledge into treatments for human disease has been slowed by the lag in our molecular understanding of human DKD.

Methods

Using our Spatial TissuE Proteomics (STEP) pipeline (comprising curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools), we imaged and analysed the expression of 21 proteins in 23 tissue sections from individuals with diabetes and healthy kidneys (n=5), compared to those with DKDIIA, IIA-B and IIB (n=2 each) and DKDIII (n=1).

Results

These analyses revealed the existence of 11 cellular clusters (kidney compartments/cell types): podocytes, glomerular endothelial cells, proximal tubules, distal nephron, peritubular capillaries, blood vessels (endothelial cells and vascular smooth muscle cells), macrophages, myeloid cells, other CD45⁺ inflammatory cells, basement membrane and the interstitium. DKD progression was associated with co-localised increases in inflammatory cells and collagen IV deposition, with concomitant loss of native proteins of each nephron segment. Cell-type frequency and neighbourhood analyses highlighted a significant increase in inflammatory cells and their adjacency to tubular and αSMA⁺ (α-smooth muscle actin-positive) cells in DKD. Finally, DKD progression showed marked regional variability within single tissue sections, as well as inter-individual variability within each DKD class.

Conclusions/interpretation

Using the STEP pipeline, we found alterations in protein expression, cellular phenotypic composition and microenvironment structure with DKD progression, demonstrating the power of this pipeline to reveal the pathophysiology of human DKD.

Graphical Abstract

中文翻译：

人类糖尿病肾病的空间蛋白质组学，从健康到 III 级

目标/假设

糖尿病肾病 (DKD) 是美国和全世界慢性和终末期肾病的主要原因。动物模型让我们了解了很多有关 DKD 机制的知识，但由于我们对人类 DKD 分子理解的滞后，将这些知识转化为人类疾病治疗方法的速度已经放缓。

方法

使用我们的空间组织蛋白质组学 (STEP) 流程（包括精选的人肾组织、多重免疫荧光和强大的分析工具），我们对糖尿病患者和健康肾脏个体 ( n =5) 的 23 个组织切片中 21 种蛋白质的表达进行了成像和分析，与 DKDIIA、IIA-B 和 IIB（各n =2）和 DKDIII（ n =1）患者相比。

结果

这些分析揭示了 11 种细胞簇（肾区室/细胞类型）的存在：足细胞、肾小球内皮细胞、近端肾小管、远端肾单位、管周毛细血管、血管（内皮细胞和血管平滑肌细胞）、巨噬细胞、骨髓细胞等CD45 ⁺炎症细胞、基底膜和间质。 DKD 进展与炎症细胞和 IV 型胶原沉积的共定位增加有关，同时伴随着每个肾单位节段天然蛋白质的损失。细胞类型频率和邻域分析强调了 DKD 中炎症细胞及其与肾小管和 αSMA ⁺ （α-平滑肌肌动蛋白阳性）细胞的邻近情况显着增加。最后，DKD 进展显示出单个组织切片内显着的区域变异性，以及每个 DKD 类别内的个体间变异性。