Cardiac and renal protective effects of 2,5-dimethylcelecoxib in angiotensin II and high-salt-induced hypertension model mice

Background:We reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling induced by sarcomeric gene mutation, left ventricular pressure overload, or β-adrenergic receptor stimulation. This effect seemed to be mediated by the inhibition of the canonical Wnt/β-catenin signaling pathway, which has been suggested to play a key role in the development of chronic kidney disease and chronic heart failure.Method:We investigated the effect of DM-celecoxib on cardiac remodeling and kidney injury in hypertension model mice induced by angiotensin II infusion in the absence or presence of high-salt load.Results:DM-celecoxib prevented cardiac remodeling and markedly reduced urinary albumin excretion without altering blood pressure in those mice. Moreover, DM-celecoxib prevented podocyte injury, glomerulosclerosis, and interstitial fibrosis in the kidney of mice loaded with angiotensin II and high-salt load. DM-celecoxib reduced the phosphorylation level of Akt and activated glycogen synthase kinase-3, which led to the suppression of the Wnt/β-catenin signal in the heart and kidney. DM-celecoxib also reduced the expression level of snail, a key transcription factor for the epithelial-mesenchymal transition and of which gene is a target of the Wnt/β-catenin signal.Conclusion:Results of the current study suggested that DM-celecoxib could be beneficial for patients with hypertensive heart and kidney diseases.