title: Differential response of bone and kidney to ACEI in db/db mice: A potential effect of captopril on accelerating bone loss.
abstract: The components of renin-angiotensin system (RAS) are expressed in the kidney and bone. Kidney disease and bone injury are common complications associated with diabetes. This study aimed to investigate the effects of an angiotensin-converting enzyme inhibitor, captopril, on the kidney and bone of db/db mice. The db/db mice were orally administered by gavage with captopril for 8weeks with db/+ mice as the non-diabetic control. Serum and urine biochemistries were determined by standard colorimetric methods or ELISA. Histological measurements were performed on the kidney by periodic acid-schiff staining and on the tibial proximal metaphysis by safranin O and masson-trichrome staining. Trabecular bone mass and bone quality were analyzed by microcomputed tomography. Quantitative polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. Captopril significantly improved albuminuria and glomerulosclerosis in db/db mice, and these effects might be attributed to the down-regulation of angiotensin II expression and the expression of its down-stream profibrotic factors in the kidney, like connective tissue growth factor and vascular endothelial growth factor. Urinary excretion of calcium and phosphorus markedly increased in db/db mice in response to captopril. Treatment with captopril induced a decrease in bone mineral density and deterioration of trabecular bone at proximal metaphysis of tibia in db/db mice, as shown in the histological and reconstructed 3-dimensional images. Even though captopril effectively reversed the diabetes-induced changes in calcium-binding protein 28-k and vitamin D receptor expression in the kidney as well as the expression of RAS components and bradykinin receptor-2 in bone tissue, treatment with captopril increased the osteoclast-covered bone surface, reduced the osteoblast-covered bone surface, down-regulated the expression of type 1 collagen and transcription factor runt-related transcription factor 2 (markers for osteoblastic functions), and up-regulated the expression of carbonic anhydrase II (marker for bone resorption). Captopril exerted therapeutic effects on renal injuries associated with type 2 diabetes but worsened the deteriorations of trabecular bone in db/db mice; the latter of which was at least in part due to the stimulation of osteoclastogenesis and the suppression of osteogenesis by captopril.
authors.affiliation: Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: medicineyan@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Li
authors.affiliation: Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Sha
authors.affiliation: Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shu
authors.affiliation: Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Xin-Luan
authors.initials: XL
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of The Hong Kong Polytechnic University, Shenzhen 518057, China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Xiao
authors.affiliation: Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
authors.forename: Man-Sau
authors.initials: MS
authors.lastname: Wong
authors.affiliation: Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: yjwang8888@126.com.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001862:Bone Resorption / Q000097:blood / Q000150:complications / Q000473:pathology* / Q000652:urine; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000009:adverse effects*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000473:pathology* / Q000652:urine; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D012333:RNA, Messenger; D000804:Angiotensin II; D002216:Captopril; D065668:Vitamin D3 24-Hydroxylase; D002118:Calcium
keywords: Bone; Captopril; Diabetes; Kidney; Osteoporosis; Renin-angiotensin system