抄録
Chronic kidney disease (CKD) is characterized by progressive, irreversible kidney damage, and the number of patients with CKD has been increasing worldwide. Several studies suggested that hypertension, dyslipidemia, and diabetes are risk factors for CKD. In this study, we generated spontaneously hypertensive and hyperlipidemic rats (SHHRs). In SHHRs, total cholesterol and plasma glucose levels become elevated when fed a high-fat, 30% sucrose diet (HFDS). However, the molecular mechanism underlying the effect of hypertensive, dyslipidemic, and hyperglycemic conditions on the kidney remains unknown. To elucidate the mechanism, we performed proteomic analysis of the kidney in SHHRs. Four-month-old male Sprague-Dawley (SD) rats and SHHRs were fed a normal diet (ND) or HFDS ad libitum for 6 months. Proteins in the renal cytoplasm were separated by LC/MS, and proteomic analysis was performed. Differentially expressed proteins were linked using Ingenuity Pathway Analysis (IPA). We identified Rho-GDP dissociation inhibitor (Rho-GDI) signaling as a candidate pathway involved in kidney injury in SHHRs with HFDS feeding. In the kidney, the levels of Rho-GDI protein and Rho GTPase-activating protein (Rho-GAP) decreased, and that of p21-activated kinase (PAK) significantly increased. In addition, the renal expression of Arhgdia (encoding Rho-GDI), Dlc1 (encoding Rho-GAP), and Pak1 (encoding PAK) genes were, at least in part, parallel to that of proteins in SHHRs that had been fed the HFDS. Furthermore, neutrophil gelatinase-associated lipocalin (Ngal), a biomarker of kidney injury, was highly expressed in the kidney of SHHRs that had been fed the HFDS. These data suggest the possibility that the Rho-GDI signaling pathway is activated in the kidney of SHHRs that are fed the HFDS, leading to kidney injury. Taken together, our findings provide a molecular basis for the effects of hypertensive, dyslipidemic, and hyperglycemic conditions on the kidney.
