Effect of Ruboxistaurin on Urinary Transforming Growth Factor-β in Patients With Diabetic Nephropathy and Type 2 Diabetes
- Richard E. Gilbert, MD, PHD12,
- Sandra A. Kim, MD, MSC1,
- Katherine R. Tuttle, MD3,
- George L. Bakris, MD4,
- Robert D. Toto, MD5,
- Janet B. McGill, MD6,
- Douglas J. Haney, PHD7,
- Darren J. Kelly, PHD2 and
- Pamela W. Anderson, MD7
- 1Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
- 2Department of Medicine, St. Vincent's Hospital, University of Melbourne, Victoria, Australia
- 3Providence Medical Research Center, Sacred Heart Medical Center, Spokane, Washington
- 4Department of Medicine, University of Chicago, Chicago, Illinois
- 5Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- 6Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
- 7Lilly Research Laboratories, Indianapolis, Indiana
- Address correspondence and reprint requests to Richard E. Gilbert, MD, PhD, St. Michael's Hospital, Room 6–138, 61 Queen St., Toronto, Ontario, Canada, M5C 2T2. E-mail: richard.gilbert{at}utoronto.ca
- ACR, albumin-to-creatinine ratio
- ARB, angiotensin receptor blocker
- PKC-β, protein kinase C-β
- RAS, renin-angiotensin system
- TCR, TGF-β–to–creatinine ratio
- TGF-β, transforming growth factor-β
Excessive protein kinase C-β (PKC-β) activity has been implicated in the pathogenesis of diabetic nephropathy (1–5) such that its selective inhibition might be a useful strategy in treating patients with this complication.
Ruboxistaurin mesylate, a bisindolylmaleimide, is a specific and selective inhibitor of PKC-β isoforms that, in preclinical studies, attenuates overexpression of transforming growth factorβ (TGF-β) (6), a key mediator of the glomerulosclerosis and tubulointerstitial fibrosis characterizing diabetic nephropathy (7).
In contrast with albuminuria, thought to derive largely from plasma filtrate, urinary TGF-β mostly reflects its intrarenal production (8). In untreated patients with diabetic nephropathy, urinary TGF-β is increased (8), parallels the magnitude of proteinuria (9), correlates with glycemia (10), and decreases with angiotensin receptor blocker (ARB) therapy (10). The effects of agents beyond those that block the renin-angiotensin system (RAS), such as PKC-β inhibition, on urinary TGF-β are unknown.
RESEARCH DESIGN AND METHODS—
We obtained urine from participants in a prospective, double-blind, placebo-controlled study of the effects of ruboxistaurin 32 mg/day in patients with diabetic nephropathy (11), in which the effect on urinary TGF-β was a prespecified secondary objective. Patients were ≥30 years old with type 2 diabetes and urinary albumin–to–creatinine ratio (ACR) 200-2000 mg/g despite stable blockade of the RAS with ACE inhibitors and/or ARBs. Urine was collected before randomization (baseline) and …
