Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene

Abstract

To evaluate the cardiovascular actions of kinins, we established a transgenic rat line harboring the human tissue kallikrein gene, TGR(hKLK1). Under the control of the zinc-inducible metallothionein promoter, the transgene was expressed in most tissues including the heart, kidney, lung, and brain, and human kallikrein was detected in the urine of transgenic animals. Transgenic rats had a lower 24-h mean arterial pressure in comparison with control rats, which was further decreased when their diet was supplemented with zinc. The day/night rhythm of blood pressure was significantly diminished in TGR(hKLK1) animals, whereas the circadian rhythms of heart rate and locomotor activity were unaffected. Induction of cardiac hypertrophy by isoproterenol treatment revealed a marked protective effect of the kallikrein transgene because the cardiac weight of TGR(hKLK1) increased significantly less, and the expression of atrial natriuretic peptide and collagen III as markers for hypertrophy and fibrosis, respectively, were less enhanced. The specific kinin-B2 receptor antagonist, icatibant, abolished this cardioprotective effect. In conclusion, the kallikrein-kinin system is an important determinant in the regulation of blood pressure and its circadian rhythmicity. It also exerts antihypertrophic and antifibrotic actions in the heart.

Bradykinin and Renal Fibrosis

“…Consistent with the anti-fibrotic effect of BK in cardiac fibrosis (29) we have recently reported that BK reduced renal fibrosis (30). Using the UUO-induced model for renal fibrosis we showed that BK B2-/-mice have significantly higher tubulointerstitial fibrosis than wild type mice.…”

In vivo bradykinin B2 receptor activation reduces renal fibrosis

“…Furthermore, the mice are housed in a pathogen-free environment. Transgenic rats overexpressing the human tissue kallikrein gene, TGR(hKLK1), and their transgene negative littermates were generated as described previously (15).…”

Cardiac Hypertrophy and Microvascular Deficit in Kinin B2 Receptor Knockout Mice

“…4 Transgenic rats overexpressing tissue kallikrein (TK) develop less cardiac hypertrophy and fibrosis than do wild-type rats. 5 In addition, evidence provided by ourselves 3 and Meneton et al 6 indicates that genetically ablating B2R or TK in 129/J mice results in dilated decompensated cardiomyopathy. This is in keeping with the recent discovery that deletion polymorphism of human B2R gene is associated with an exaggerated cardiac growth response to physical training in healthy volunteers.…”