Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Front Immunol. 2023 Aug 22;14:1222339. doi: 10.3389/fimmu.2023.1222339. eCollection 2023.
Even during physiologic aging, the kidney experiences a loss of mass and a progressive functional decline. This is clinically relevant as it leads to an increased risk of acute and chronic kidney disease. The kidney tubular system plays an important role in the underlying aging process, but the involved cellular mechanisms remain largely elusive.
Kidneys of 3-, 12- and 24-month-old male C57BL/6J mice were used for RNA sequencing, histological examination, immunostaining and RNA-in-situ-hybridization. Single cell RNA sequencing data of differentially aged murine and human kidneys was analyzed to identify age-dependent expression patterns in tubular epithelial cells. Senescent and non-senescent primary tubular epithelial cells from mouse kidney were used for in vitro experiments.
During normal kidney aging, tubular cells adopt an inflammatory phenotype, characterized by the expression of MHC class II related genes. In our analysis of bulk and single cell transcriptional data we found that subsets of tubular cells show an age-related expression of Cd74, H2-Eb1 and H2-Ab1 in mice and CD74, HLA-DQB1 and HLADRB1 in humans. Expression of MHC class II related genes was associated with a phenotype of tubular cell senescence, and the selective elimination of senescent cells reversed the phenotype. Exposure to the Cd74 ligand MIF promoted a prosenescent phenotype in tubular cell cultures.
Together, these data suggest that during normal renal aging tubular cells activate a program of 'tubuloinflammaging', which might contribute to age-related phenotypical changes and to increased disease susceptibility.
即使在生理衰老过程中，肾脏也会经历质量损失和功能逐渐下降。这在临床上很重要，因为它会增加急性和慢性肾脏病的风险。肾脏管状系统在潜在的衰老过程中起着重要作用，但涉及的细胞机制在很大程度上仍未被揭示。
使用 3 个月、12 个月和 24 个月大的雄性 C57BL/6J 小鼠的肾脏进行 RNA 测序、组织学检查、免疫染色和 RNA 原位杂交。分析差异老化的鼠类和人类肾脏的单细胞 RNA 测序数据，以鉴定管状上皮细胞中与年龄相关的表达模式。使用来自小鼠肾脏的衰老和非衰老的原代管状上皮细胞进行体外实验。
在正常肾脏衰老过程中，管状细胞呈现出炎症表型，其特征是 MHC Ⅱ类相关基因的表达。在我们对批量和单细胞转录数据的分析中，我们发现小鼠的肾小管细胞存在与年龄相关的 Cd74、H2-Eb1 和 H2-Ab1 以及人类的 CD74、HLA-DQB1 和 HLADRB1 的表达。MHC Ⅱ类相关基因的表达与管状细胞衰老的表型相关，选择性消除衰老细胞可逆转该表型。暴露于 Cd74 配体 MIF 可促进管状细胞培养物中的衰老前表型。
综上所述，这些数据表明，在正常的肾脏衰老过程中，肾小管细胞激活了“小管炎衰老”程序，这可能导致与年龄相关的表型变化和增加疾病易感性。
