Targeting RAC1 might be a potential therapeutic strategy for diabetic kidney disease: a Mendelian randomization...

Area of Science:

• Nephrology
• Genetics
• Pharmacology

Background:

• Diabetic kidney disease (DKD) is a major complication of diabetes.
• Identifying genetic factors influencing DKD is crucial for developing targeted therapies.
• Ras-related C3 botulinum toxin substrate 1 (RAC1) is implicated in cellular processes relevant to kidney function.

Purpose of the Study:

• To investigate the causal association between RAC1 genetic variants and the risk and progression of DKD.
• To explore the role of RAC1 in the development of end-stage renal disease (ESRD), albuminuria, and estimated glomerular filtration rate (eGFR) decline in diabetic individuals.

Main Methods:

• Utilized Mendelian randomization analysis with expression quantitative trait loci (eQTL) data for RAC1 expression.
• Assessed outcomes including DKD incidence, ESRD risk, urinary albumin-to-creatinine ratio (ACR), and eGFR in individuals with diabetes.
• Employed inverse variance weighted (IVW), weighted median, and MR-PRESSO methods, alongside sensitivity analyses for heterogeneity and pleiotropy.

Main Results:

• Found a significant causal association between genetically predicted RAC1 activation and increased risk of DKD (OR=1.28, P=0.004).
• Demonstrated a causal link between elevated RAC1 expression and higher risk of ESRD (OR=1.20, P=0.032) and increased albuminuria (β=0.052, P=0.036).
• No significant causal relationship was observed for RAC1 and eGFR, with notable heterogeneity and pleiotropy.

Conclusions:

• Genetic activation of RAC1 is causally associated with higher incidence of DKD, increased risk of ESRD, and exacerbated albuminuria in diabetic patients.
• Targeting RAC1 presents a potential therapeutic strategy for managing and treating diabetic kidney disease.