游离泛素在2型糖尿病患者糖尿病肾病识别中的临床价值及其保护作用的初步探索

Clinical value of free ubiquitin in the identification of diabetic nephropathy in patients with type 2 diabetes mellitus and preliminary exploration of its protective effect.

作者信息

Bian Jing, Li Jianhui, Zhou Lina, Cao Yue, Fang Jinhui

机构信息

Clinical Laboratory, The Second Hospital of Heilongjiang Province, Harbin, 150000, China.

Department of Medical Administration, The Second Hospital of Heilongjiang Province, Harbin, 150000, China.

出版信息

BMC Nephrol. 2025 Jul 17;26(1):395. doi: 10.1186/s12882-025-04219-8.

DOI:10.1186/s12882-025-04219-8

PMID:40676522

Abstract

OBJECTIVE

Free ubiquitin (Ub) is crucial in various cellular processes. Recent studies suggest that alterations in free Ub levels may be closely associated with the development of diabetes. However, its levels and functional role in diabetic nephropathy (DN) remain unclear. This study investigated the potential of the serum free Ub level as a biomarker for distinguishing DN from non-nephrotic type 2 diabetes mellitus (T2DM) and its underlying mechanisms in DN pathogenesis.

METHODS

The type 2 diabetic nephropathy (T2DN, n = 74) and T2DM (n = 176) patients visited the hospital between September 2021 and September 2023 were retrospectively analyzed, with clinical indicators collected. The correlation between serum free Ub level and renal function indicators [serum uric acid (SUA), blood urea nitrogen (BUN), serum creatinine (Scr), cystatin C (Cys-C), urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR)], the independent correlation between serum free Ub expression and T2DN occurrence, and the diagnostic value of serum free Ub expression for early T2DN occurrence in T2DM patients were analyzed by Spearman, Logistic regression, and receiver operating characteristic analyses. The high glucose (HG)-induced renal tubular epithelial cell (HK-2 cell) injury model was treated with different concentrations of free Ub. HK-2 cell viability, proliferation and apoptosis, apoptosis-related protein expression, and interleukin (IL)-6 and IL-1β concentrations were assessed by CCK-8, EdU staining, flow cytometry, western blot and ELISA.

RESULTS

Compared to the T2DM group, the T2DN group exhibited significantly reduced serum free Ub levels, elevated levels of SUA, BUN, Scr, Cys-C, and UACR, and decreased eGFR levels. Serum free Ub levels in the T2DN group were negatively correlated with SUA, BUN, Scr, Cys-C, and UACR, and positively correlated with eGFR. Serum free Ub was an independent influencing factor and had high diagnostic value for early T2DN occurrence in T2DM patients. After HG (30 mM) treatment, HK-2 cell viability was significantly reduced, cell proliferation was suppressed, and apoptosis was increased, while subsequent free Ub treatment reversed these effects of HG on cell viability, proliferation, and apoptosis.

CONCLUSION

Our data suggest that serum free Ub could predict early T2DN occurrence and protect proxìmal tubule cells from HG-induced apoptosis.

摘要

目的

游离泛素（Ub）在多种细胞过程中至关重要。近期研究表明，游离Ub水平的改变可能与糖尿病的发生密切相关。然而，其在糖尿病肾病（DN）中的水平及功能作用仍不清楚。本研究探讨血清游离Ub水平作为区分DN与非肾病型2型糖尿病（T2DM）生物标志物的潜力及其在DN发病机制中的潜在机制。

方法

回顾性分析2021年9月至2023年9月期间就诊的2型糖尿病肾病（T2DN，n = 74）和T2DM（n = 176）患者，收集临床指标。采用Spearman分析、Logistic回归分析和受试者工作特征分析血清游离Ub水平与肾功能指标[血清尿酸（SUA）、血尿素氮（BUN）、血清肌酐（Scr）、胱抑素C（Cys-C）、尿白蛋白与肌酐比值（UACR）、估算肾小球滤过率（eGFR）]之间的相关性、血清游离Ub表达与T2DN发生的独立相关性以及血清游离Ub表达对T2DM患者早期T2DN发生的诊断价值。用不同浓度的游离Ub处理高糖（HG）诱导的肾小管上皮细胞（HK-2细胞）损伤模型。通过CCK-8、EdU染色、流式细胞术、蛋白质免疫印迹法和酶联免疫吸附测定法评估HK-2细胞活力、增殖和凋亡、凋亡相关蛋白表达以及白细胞介素（IL）-6和IL-1β浓度。

结果

与T2DM组相比，T2DN组血清游离Ub水平显著降低，SUA、BUN、Scr、Cys-C和UACR水平升高，eGFR水平降低。T2DN组血清游离Ub水平与SUA、BUN、Scr、Cys-C和UACR呈负相关，与eGFR呈正相关。血清游离Ub是T2DM患者早期T2DN发生的独立影响因素，具有较高诊断价值。HG（30 mM）处理后，HK-2细胞活力显著降低，细胞增殖受到抑制，凋亡增加，而随后的游离Ub处理逆转了HG对细胞活力、增殖和凋亡的这些影响。