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Experimental kallikrein gene therapy in hypertension, cardiovascular and renal diseases
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Insights
Somatic gene therapy using human tissue kallikrein (hK) DNA effectively lowers blood pressure in hypertensive rats. This approach shows promise for treating hypertension and related cardiovascular and renal disorders.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Hypertension affects 25% of the population and increases risk for cardiovascular diseases.
- Somatic gene delivery offers a potential therapeutic strategy for complex disorders like hypertension.
Purpose of the Study:
- To investigate the therapeutic potential of somatic gene delivery of human tissue kallikrein (hK) for treating hypertension.
- To evaluate the efficacy of different delivery methods (naked DNA, adenovirus vector) and routes for hK gene transfer in hypertensive rat models.
Main Methods:
- Delivery of hK DNA constructs (naked or adenovirus-mediated) via various routes (intramuscular, intravenous, etc.) into different hypertensive rat models.
- Assessment of blood pressure reduction, hK expression in tissues (RT-PCR, ELISA), and organ damage markers (histology).
- Validation of hypotensive effects using aprotinin, a kallikrein inhibitor.
Main Results:
- A single hK DNA injection caused sustained blood pressure reduction in spontaneously hypertensive rats.
- Adenovirus-mediated hK gene delivery rapidly and effectively lowered blood pressure in multiple hypertensive rat models.
- hK gene delivery attenuated kidney damage and reduced cardiac hypertrophy in Dahl salt-sensitive rats on a high-salt diet.
Conclusions:
- Somatic gene delivery of hK is a feasible and effective strategy for managing hypertension.
- hK gene therapy demonstrates broad benefits, including cardiovascular and renal protection, making it a promising treatment for salt-related disorders.
Abstract:
Hypertension is a multi-gene and multi-factorial disorder affecting about 25% of the population. Hypertensive subjects are more likely to develop other cardiovascular diseases such as peripheral vascular disease, coronary heart disease, congestive heart failure and cerebrovascular disease. To demonstrate potential therapeutic effects of somatic gene delivery in treating hypertension, we delivered human tissue kallikrein in the form of naked DNA or in an adenovirus vector into hypertensive rats. Naked DNA constructs were delivered into spontaneously hypertensive rats via intramuscular, intravenous, intraportal vein and intraperitoneal routes. A single injection of human kallikrein DNA construct caused a sustained reduction of blood pressure which began 1 week post-injection and continued for more than 6 weeks. The hypotensive effect caused by somatic gene delivery of human tissue kallikrein in hypertensive rats is reversed by aprotinin, a potent tissue kallikrein inhibitor. Both systemic and local delivery of the human tissue kallikrein gene in an adenovirus vector were found to be highly effective in producing a rapid and sustained reduction of blood pressure in hypertensive rat models such as spontaneously hypertensive rats; two kidney, one clip Goldblatt hypertensive rats; and Dahl salt-sensitive rats. The expression of human tissue kallikrein in rats was identified in the heart, kidney, aorta, lung and liver by reverse transcription-polymerase chain reaction followed by Southern blot analysis and by ELISA. Adenovirus-mediated kallikrein gene delivery also resulted in the attenuation of glomerular and tubular damage and reduction of the left ventricular mass and cardiomyocyte size in Dahl salt-sensitive rats fed a high salt diet. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating salt-related hypertension as well as cardiovascular and renal diseases. These results suggest the feasibility of applying somatic gene therapy for treating hypertension and salt-related cardiovascular and renal disorders.