Free radical biology & medicine · 2026
Urinary retinol-binding protein 4 as a noninvasive indicator of tubular ferroptosis in diabetic kidney disease.
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Jia Ruoyu, Tan Rong, Qian Bin, Tang Bihui, Zhong Yongzhong, Yu Hui, Qiao Ziyang, Ma Lei, Li Limin, Zeng Caihong
Аннотация
BACKGROUND: Tubular ferroptosis is increasingly implicated in diabetic kidney disease (DKD), but noninvasive urinary biomarkers reflecting ferroptosis-related tubular injury remain limited. This study investigated whether urinary retinol-binding protein 4 (RBP4) reflects tubular ferroptosis in DKD.
METHODS: We integrated matched single-cell transcriptomic, urinary proteomic, and clinicopathological data from the Kidney Precision Medicine Project (KPMP), a single-center biopsy-proven DKD transcriptomic cohort with longitudinal follow-up, and a high-fat diet/streptozotocin-induced diabetic kidney injury mouse model. A direction-weighted tubular ferroptosis score was constructed using ACSL4, GPX4, FTH1, and SLC3A2. Associations among urinary RBP4, ferroptosis score, clinicopathological parameters, and renal outcomes were assessed using correlation analysis, regression models, Kaplan-Meier analysis, and Cox proportional hazards models. Liproxstatin-1 was used to examine whether ferroptosis inhibition altered urinary RBP4 and renal injury in diabetic mice.
RESULTS: In both the KPMP and local cohorts, tubular ferroptosis scores were increased in DKD and were associated with proteinuria, estimated glomerular filtration rate (eGFR), interstitial fibrosis and tubular atrophy, tubular injury, and interstitial inflammation. Urinary RBP4 showed consistent associations with the ferroptosis score and multiple clinicopathological injury indicators, whereas kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) showed weaker and less consistent associations. Higher urinary RBP4 quartiles were associated with a stepwise decline in renal event-free survival, and urinary RBP4 remained associated with renal progression and ferroptosis score after adjustment for baseline clinical factors and 24-h proteinuria. Within the available measurements, adjustment for serum transthyretin (TTR) or circulating RBP4 did not materially alter the urinary RBP4-ferroptosis association. In diabetic mice, Liproxstatin-1 attenuated tubular lipid peroxidation, restored the glutathione/malondialdehyde balance, reduced tubulointerstitial injury, and decreased urinary RBP4.
CONCLUSION: Urinary RBP4 is closely associated with tubular ferroptosis-related injury, clinicopathological damage, and renal progression in DKD. It may serve as a noninvasive indicator for identifying ferroptosis-related tubular injury phenotypes and stratifying DKD progression risk.
METHODS: We integrated matched single-cell transcriptomic, urinary proteomic, and clinicopathological data from the Kidney Precision Medicine Project (KPMP), a single-center biopsy-proven DKD transcriptomic cohort with longitudinal follow-up, and a high-fat diet/streptozotocin-induced diabetic kidney injury mouse model. A direction-weighted tubular ferroptosis score was constructed using ACSL4, GPX4, FTH1, and SLC3A2. Associations among urinary RBP4, ferroptosis score, clinicopathological parameters, and renal outcomes were assessed using correlation analysis, regression models, Kaplan-Meier analysis, and Cox proportional hazards models. Liproxstatin-1 was used to examine whether ferroptosis inhibition altered urinary RBP4 and renal injury in diabetic mice.
RESULTS: In both the KPMP and local cohorts, tubular ferroptosis scores were increased in DKD and were associated with proteinuria, estimated glomerular filtration rate (eGFR), interstitial fibrosis and tubular atrophy, tubular injury, and interstitial inflammation. Urinary RBP4 showed consistent associations with the ferroptosis score and multiple clinicopathological injury indicators, whereas kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) showed weaker and less consistent associations. Higher urinary RBP4 quartiles were associated with a stepwise decline in renal event-free survival, and urinary RBP4 remained associated with renal progression and ferroptosis score after adjustment for baseline clinical factors and 24-h proteinuria. Within the available measurements, adjustment for serum transthyretin (TTR) or circulating RBP4 did not materially alter the urinary RBP4-ferroptosis association. In diabetic mice, Liproxstatin-1 attenuated tubular lipid peroxidation, restored the glutathione/malondialdehyde balance, reduced tubulointerstitial injury, and decreased urinary RBP4.
CONCLUSION: Urinary RBP4 is closely associated with tubular ferroptosis-related injury, clinicopathological damage, and renal progression in DKD. It may serve as a noninvasive indicator for identifying ferroptosis-related tubular injury phenotypes and stratifying DKD progression risk.