High serum uric acid is linked with diabetic kidney disease progression: Evidence from Mendelian randomization analysis and animal study.

BACKGROUND

Diabetic kidney disease (DKD) is a serious condition associated with diabetes, and the role of uric acid (UA) in its development remains debated.

METHODS

This study used a Mendelian randomization (MR) analysis, epidemiological validation, transcriptome data mining and animal study to assess the causal relationship between high serum uric acid (HUA) and DKD. Meanwhile, differential expression analysis of lactate-related genes were conducted. Besides, the suggested lactylation associated genes was verified in vivo and vitro.

RESULTS

MR shows that gene-predicted serum uric acid level was positively correlated with the risk of DKD (OR = 1.25, 95% CI: 1.01-1.54, P = 0.0396). The finding was further supported by US National Health and Nutrition Survey data. Lactylation associated transcriptome analysis identified associated genes, HMOX1, OGDH, and SPP1. In type 1 and type 2 diabetes HUA mouse model, the expression of HMOX1, OGDH, and SPP1 was significantly enhanced and HUA treatment significantly aggravated renal injury. In podocyte cell line, inhibition of the expression of HMOX1, OGDH, and SPP1 significantly improve the podocyte function.

CONCLUSIONS

This study provides evidence that high serum uric acid is associated with DKD, and indicates HMOX1, OGDH, and SPP1 as possible important molecules linked to disease progression. These findings offer new biomarkers and potential therapeutic targets for early diagnosis and intervention of DKD.