Published Online
on July 22, 2002

A more recent version of this article appeared on August 20, 2002

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Submitted on March 19, 2002
Revised on May 22, 2002
Accepted on May 23, 2002

Prevention of Diabetes-Induced Microangiopathy by Human Tissue Kallikrein Gene Transfer

Costanza Emanueli PhD, Maria B. Salis PharmD, Alessandra Pinna BS, Tiziana Stacca BS, Anna F. Milia PharmD, Alessandra Spano PhD, Julie Chao PhD, Lee Chao PhD, Luigi Sciola BS, and Paolo Madeddu MD^*

From Cardiovascular Medicine and Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems (INBB) (C.E., M.B.S., A.P., T.S., A.F.M., A.S., P.M.), Osilo, Italy; Internal Medicine (P.M.) and Physiological, Biochemical and Cellular Sciences (A.S., L.S.), University of Sassari, Sassari, Italy; and Department of Biochemistry and Molecular Biology (J.C, L.C.), Medical University of South Carolina, Charleston, SC.

^* To whom correspondence should be addressed. E-mail: madeddu{at}yahoo.com.

Background—Microvascular insufficiency represents a major cause of end-organ failure among diabetics.

Methods and Results—In streptozotocin-induced diabetic mice, we evaluated the potential of human tissue kallikrein (hTK) gene as a sole therapy against peripheral microangiopathy. Local delivery of hTK gene halted the progression of microvascular rarefaction in hindlimb skeletal muscle by inhibiting apoptosis, thus ensuring an improved hemodynamic recovery in case of supervening vascular occlusion. The curative action of hTK did not necessitate insulin supplementation. Application of gene therapy at a stage of established microangiopathy stimulated vascular regeneration.

Conclusions—Our studies indicate that hTK may represent a useful tool for the treatment of microvascular complications in diabetics.

Key words: diabetes mellitus • microangiopathy • gene therapy • angiogenesis • apoptosis

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