Abstract
Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model) or sham operation were treated for 2 weeks with a normal-(0.4% NaCl), or high-salt (4% NaCl) diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54%) phosphopeptides upregulated and 76 (46%) phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49%) phosphopeptides and downregulation of 88 (51%) phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed.
Highlights
Chronic kidney disease (CKD) is a global public health problem affecting over 10.8% or 13% of western [1] or Chinese population, respectively [2]
Cardiovascular diseases occur in progressive stages of chronic renal failure[7], in which besides the conventional cardiovascular risk factors, many factors more specific to CKD, such as proteinuria, anaemia, left ventricular hypertrophy, arterial calcification, abnormal calcium/phosphate/ vitamin D homeostasis and inflammation contribute to cardiovascular risk [8]
Given that one of the major goals of this project was to identify phosphoproteins that may be contributing to salt-induced heart damage, we examined expression of phospho-lamin A and phospho-phospholamban as well as their downstream genes desmin and SERCA2a, which altered significantly in response to high salt intake in chronic renal failure (CRF) rats
Summary
Chronic kidney disease (CKD) is a global public health problem affecting over 10.8% or 13% of western [1] or Chinese population, respectively [2]. A large number of observational studies have demonstrated excess cardiovascular risks associated with CKD [3,4,5]. Conventional cardiovascular risk factors such as hypertension and diabetes are highly prevalent in patients with CKD and end-stage renal disease. Cardiovascular diseases occur in progressive stages of chronic renal failure[7], in which besides the conventional cardiovascular risk factors, many factors more specific to CKD, such as proteinuria, anaemia, left ventricular hypertrophy, arterial calcification, abnormal calcium/phosphate/ vitamin D homeostasis and inflammation contribute to cardiovascular risk [8]. Heart damage is widely present in patients with CKD, but the mechanisms underlying CKD-induced heart damage remains unclear
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