Zhifeng Dong1, Kaizheng Gong2, Dong Huang1, Wei Zhu1, Wanfeng Sun3, Ying Zhang4, Ping Xin1, Yuan Shen3, Penglong Wu1, Jingbo Li1, Zhigang Lu1, Xiaoming Zhang5, Meng Wei6. 1. Department of Cardiology, Shanghai Sixth Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China. 2. Department of Cardiology, The Second Clinical Medical College, Yangzhou University, Yangzhou 225001, China. 3. Affiliated Yancheng Hospital of Medical School, Southeast University, Yancheng 224001, China. 4. Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. 5. Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: xmzhang@ips.ac.cn. 6. Department of Cardiology, Shanghai Sixth Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China. Electronic address: weimeng19570101@126.com.
Abstract
BACKGROUND: Clinically, approximately one-third of patients with chronic heart failure (CHF) exhibit some degree of renal dysfunction. This renal dysfunction is referred to as cardiorenal syndrome (CRS) and plays an important role in the poor prognosis of CHF. Mounting evidence suggests that diabetes is the most common underlying risk factor for CRS. However, the underlying pathophysiological mechanisms are poorly understood. METHODS: We performed the following comparisons in two separate protocols: 1) surgically induced myocardial infarction rats (MI, n=10), sham operation rats (Ctr, n=10) and MI rats treated with Fasudil, a Rho-kinase inhibitor (MI+Fas, n=9); and 2) STZ-induced type 1 diabetic rats (DB, n=10), DB+MI rats (n=10) and DB+MI rats treated with Fasudil (DB+MI+Fas, n=9). Renal hemodynamics and vasoconstrictor reactivity were evaluated using the DMT myograph system. Renal immunity was evaluated by flow cytometry, electron microscopy, immunofluorescence, etc. RESULTS: Twelve weeks after the operation, compared with DB or MI rats, DB+MI rats exhibited the following characteristics: 1) significantly increased glomerular enlargement, fibrosis, glomerulosclerosis, podocyte injury and microalbuminuria; 2) significantly increased vasoconstrictor reactivity of the renal interlobular arteries and renal venous pressure; 3) significantly increased infiltration of CD₃+ and CD₄+ T cells and decreased Treg/Th17 ratios; and 4) significantly increased glomerular deposition of IgG and C₄. In contrast, rats with MI only showed mildly accelerated glomerular remodeling and microalbuminuria, with little change in renal hemodynamics and immunity. Fasudil treatment significantly improved the renal lesions in DB+MI rats but not MI rats. CONCLUSIONS: Post-MI cardiac dysfunction significantly accelerated glomerular remodeling, podocyte injury and microalbuminuria in STZ-induced diabetic rats. These changes were accompanied by altered local hemodynamics and immunity.
BACKGROUND: Clinically, approximately one-third of patients with chronic heart failure (CHF) exhibit some degree of renal dysfunction. This renal dysfunction is referred to as cardiorenal syndrome (CRS) and plays an important role in the poor prognosis of CHF. Mounting evidence suggests that diabetes is the most common underlying risk factor for CRS. However, the underlying pathophysiological mechanisms are poorly understood. METHODS: We performed the following comparisons in two separate protocols: 1) surgically induced myocardial infarctionrats (MI, n=10), sham operation rats (Ctr, n=10) and MI rats treated with Fasudil, a Rho-kinase inhibitor (MI+Fas, n=9); and 2) STZ-induced type 1 diabeticrats (DB, n=10), DB+MI rats (n=10) and DB+MI rats treated with Fasudil (DB+MI+Fas, n=9). Renal hemodynamics and vasoconstrictor reactivity were evaluated using the DMT myograph system. Renal immunity was evaluated by flow cytometry, electron microscopy, immunofluorescence, etc. RESULTS: Twelve weeks after the operation, compared with DB or MI rats, DB+MI rats exhibited the following characteristics: 1) significantly increased glomerular enlargement, fibrosis, glomerulosclerosis, podocyte injury and microalbuminuria; 2) significantly increased vasoconstrictor reactivity of the renal interlobular arteries and renal venous pressure; 3) significantly increased infiltration of CD₃+ and CD₄+ T cells and decreased Treg/Th17 ratios; and 4) significantly increased glomerular deposition of IgG and C₄. In contrast, rats with MI only showed mildly accelerated glomerular remodeling and microalbuminuria, with little change in renal hemodynamics and immunity. Fasudil treatment significantly improved the renal lesions in DB+MI rats but not MI rats. CONCLUSIONS: Post-MI cardiac dysfunction significantly accelerated glomerular remodeling, podocyte injury and microalbuminuria in STZ-induced diabeticrats. These changes were accompanied by altered local hemodynamics and immunity.