Amid the rapidly rising number of people with diabetes worldwide, the prevalence of
diabetic kidney disease (DKD) is expected to increase considerably despite available treatments. Consequently, novel therapeutic agents are urgently needed.
Ruboxistaurin mesylate is a
bisindolylmaleimide that specifically inhibits the beta
isoform of
protein kinase C (PKC). In experimental models of DKD,
ruboxistaurin normalized glomerular hyperfiltration, decreased urinary
albumin excretion, preserved kidney function, and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial
fibrosis. These beneficial effects of
ruboxistaurin, both alone and combined with renin-angiotensin system inhibition, have been observed in a variety of experimental models of DKD. A phase 2 study of
PKC-beta inhibition in persons with
type 2 diabetes and DKD already treated with
angiotensin converting enzyme inhibition and/or
angiotensin receptor blockade has been conducted. Addition of
ruboxistaurin for 1 year reduced urinary
albumin, prevented an increase in urinary
transforming growth factor-beta, and stabilized estimated glomerular filtration rate. Based on secondary analyses of clinical trials in patients with
diabetic retinopathy or neuropathy,
ruboxistaurin appears safe and may also prevent onset of DKD.
PKC-beta inhibition holds promise as a new strategy to improve
kidney disease outcomes in diabetes. Large-scale clinical trials will be required to confirm safety and to validate prospective benefits of
ruboxistaurin on relevant clinical endpoints in DKD.