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Updated: Aug 13, 2026
Improved Renal Denervation Mitigated Hypertension Induced by Angiotensin II Infusion
Published on: May 26, 2022
Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats
Mark W M Schellings1, Marcus Baumann, Rick E W van Leeuwen
1Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, The Netherlands.
Abstract:
Imatinib specifically inhibits receptor tyrosine kinase signaling and is clinically used to treat leukemia. Receptor tyrosine kinases not only mediate tumor growth but also initiate adverse signaling in heart failure. We investigated whether imatinib, by inhibiting the platelet-derived growth factor receptor-beta (PDGFRbeta), prevents cardiac and renal damage in TGR(mRen2)27 (Ren2) rats. Eight-week-old male homozygous Ren2 and Sprague Dawley rats were treated either with imatinib (30 mg/kg; STI-571) or placebo for 8 weeks (Ren2 n=12 for each group; Sprague Dawley n=6 for each group). Imatinib did not affect blood pressure or left ventricular (LV) hypertrophy in both groups. Imatinib attenuated the decline in fractional shortening (imatinib versus Ren2 placebo 45+/-4.5% versus 32+/-3%; n=7-11; P<0.05) and in diastolic function in Ren2 rats (baseline diastolic dP/dt corrected for systolic blood pressure Ren2 imatinib versus Ren2 placebo 38.6+/-0.67 versus 35.3+/-0.41 [1 . s(-1)]; n=7-11; P<0.05). This was associated with decreased cardiac fibrosis and decreased activation of PDGFRbeta and extracellular signal-regulated kinase 1/2. Renal microvascular hypertrophy and perivascular fibrosis in Ren2 rats were significantly decreased by imatinib. In vitro, imatinib blocked angiotensin II-induced activation of the PDGFRbeta and significantly decreased fibroblast proliferation and collagen production. In conclusion, imatinib did not affect LV hypertrophy but attenuated the decline in cardiac function and reduced renal microvascular damage associated with reduced activation of the PDGFRbeta. The simultaneous improvement in both heart and kidneys suggests that inhibition of the PDGFRbeta has broad protective effects that may provide novel avenues for a blood pressure-independent protection against end-organ damage.
Insights
Imatinib treatment, by inhibiting platelet-derived growth factor receptor-beta (PDGFRbeta), improved cardiac function and reduced kidney damage in rats, offering potential blood pressure-independent protection against organ damage.
Area of Science:
- Cardiovascular Research
- Nephrology
- Pharmacology
Background:
- Receptor tyrosine kinases mediate tumor growth and adverse signaling in heart failure.
- Imatinib is a tyrosine kinase inhibitor used to treat leukemia.
- Platelet-derived growth factor receptor-beta (PDGFRbeta) signaling is implicated in cardiac and renal damage.
Purpose of the Study:
- To investigate if imatinib, by inhibiting PDGFRbeta, prevents cardiac and renal damage in TGR(mRen2)27 (Ren2) rats.
- To assess the effects of imatinib on cardiac function, cardiac fibrosis, and renal microvascular damage.
- To explore the in vitro effects of imatinib on angiotensin II-induced PDGFRbeta activation, fibroblast proliferation, and collagen production.
Main Methods:
- Male Ren2 and Sprague Dawley rats were treated with imatinib (30 mg/kg) or placebo for 8 weeks.
- Cardiac function was assessed by measuring fractional shortening and diastolic function.
- Cardiac fibrosis, renal microvascular hypertrophy, and perivascular fibrosis were evaluated.
- In vitro studies examined imatinib's effect on angiotensin II-stimulated PDGFRbeta activation and fibroblast activity.
Main Results:
- Imatinib did not affect blood pressure or left ventricular hypertrophy in either rat group.
- Imatinib attenuated the decline in cardiac fractional shortening and diastolic function in Ren2 rats.
- Imatinib decreased cardiac fibrosis, PDGFRbeta activation, and extracellular signal-regulated kinase 1/2 activation.
- Renal microvascular hypertrophy and perivascular fibrosis were significantly reduced by imatinib.
- In vitro, imatinib blocked angiotensin II-induced PDGFRbeta activation and reduced fibroblast proliferation and collagen production.
Conclusions:
- Imatinib attenuated cardiac dysfunction and reduced renal microvascular damage in Ren2 rats, independent of blood pressure effects.
- Inhibition of PDGFRbeta by imatinib demonstrated broad protective effects against cardiac and renal end-organ damage.
- These findings suggest novel avenues for blood pressure-independent protection against organ damage through PDGFRbeta inhibition.
