Exposure to Cigarette Smoke Worsens Chronic Kidney Disease Induced Cardiac Hypertrophy and Fibrosis

Abstract

IntroductionAlthough smoking accelerates renal and cardiac disease progression, the mechanisms by which it does so are unclear. Previously our lab has found that platelet activation can lead to increased renal injury. As smoking is a well‐known cause of platelet activation we postulated that smoking would accelerate renal disease progression as well as the associated cardiomyopathy in experimental renal failure.MethodsWe used male Sprague‐Dawley rats which were divided into two surgical groups one receiving sham (control) operations the other receiving the 5/6th partial nephrectomy (PNx) operation, a model of Chronic Kidney Disease (CKD). Each surgical group of animals were further split into two groups, one receiving exposure to side stream smoke from five 3R4F combustible cigarettes, delivered over 4 hours per day, 5 days per week for 4 weeks and non‐exposed controls. Blood pressure via tail cuff, renal and cardiac fibrosis, proteinuria, cardiac ejection fraction and Western blots to evaluate CD40 expression in kidney were analyzed 4 weeks following the start of the procedure.ResultsPNx increases systolic blood pressure compared to sham controls (177±16 vs 128±6 mmHg, p<0.05). Cigarette smoke exposure also increased blood pressure in Sham operated animals (142±3 mmHg, p<0.05) and with PNx (191±10 mmHg, p<0.05). PNx alone increased cardiac and renal fibrosis by 2.7‐ and 8.7 fold, respectively (p<0.01) versus sham‐operated animals. Cigarette smoking worsened cardiac and renal fibrosis (4.4‐ and 9.4‐fold, p<0.01) in Sham operated animals. Additionally, smoking significantly increased cardiac and renal fibrosis in PNx‐operated animals, resulting in 2.5‐ and 2.4‐fold higher fibrosis.Proteinuria increased significantly with PNx alone vs shams (p<0.05). Smoke exposure doubled proteinuria in PNx (p<0.05), a similar trend was not observed in sham animals exposed to smoke vs those that were not. Ejection fraction as determined by echocardiography and cardiac hypertrophy as measured by heart weight to body weight ratio increased significantly in PNx operated animals versus shams (p<0.01) and smoking induced further significant increases in ejection fraction and cardiac hypertrophy vs non‐exposed animals (p<0.01). Finally, western blot analysis revealed that PNx and smoking both individually increased kidney expression of the pro‐inflammatory molecule CD40 and when combined synergized to increase CD40 protein expression over that observed for either treatment alone.ConclusionsCombustible cigarette smoking significantly worsens progression of experimental cardiac and renal fibrosis and hypertrophy.Support or Funding InformationThis work was supported by NIH grant R01 HL‐105649 and F32 DK‐104615