Semaphorin 3A (
sema3A) was recently identified as an early diagnostic
biomarker of
acute kidney injury. However, its role as a
biomarker and/or mediator of
chronic kidney disease (CKD) related to
diabetic nephropathy is unknown. We examined the expression of
sema3A in diabetic animal models and in humans and tested whether
sema3A plays a pathogenic role in the development of
diabetic nephropathy. The expression of
sema3A was localized to podocytes and epithelial cells in distal tubules and collecting ducts in control animals, and its expression was increased following the induction of diabetes. Quantification of
sema3A urinary excretion in three different diabetic mouse models showed that excretion was increased as early as 2 weeks after the induction of diabetes and increased over time, in conjunction with the development of nephropathy. Consistent with the mouse data, increased
sema3A urinary excretion was detected in diabetic patients with
albuminuria, particularly in those with macroalbuminuria. Genetic ablation of
sema3A or pharmacological inhibition with a novel
sema3A inhibitory
peptide was protected against diabetes-induced
albuminuria, kidney
fibrosis,
inflammation, oxidative stress, and renal dysfunction. We conclude that
sema3A is both a
biomarker and a mediator of
diabetic kidney disease and could be a promising therapeutic target in
diabetic nephropathy. Key messages Diabetes induced
sema3A excretion in urine. Increased
semaphorin 3A was associated with severity of
albuminuria. Seme3A-mediated diabetes induced glomerulosclerosis.
Peptide-based inhibition of semaphorin3A suppressed
diabetic nephropathy.