Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats: a role for KLF15.
Dietary protein restriction is an important treatment for chronic kidney disease. Herein, we tested the effect of low-protein or low-protein plus ketoacids (KA) diet in a remnant kidney model. Rats with a remnant kidney were randomized to receive normal protein diet (22%), low-protein (6%) diet (LPD), or low-protein (5%) plus KA (1%) diet for 6 months. Protein restriction prevented proteinuria, decreased blood urea nitrogen levels, and renal lesions; however, the LPD retarded growth and decreased serum albumin levels. Supplementation with KA corrected these abnormalities and provided superior renal protection compared with protein restriction alone. The levels of Kruppel-like factor-15 (KLF15), a transcription factor shown to reduce cardiac fibrosis, were decreased in remnant kidneys. Protein restriction, which increased KLF15 levels in the normal kidney, partially recovered the levels of KLF15 in remnant kidney. The expression of KLF15 in mesangial cells was repressed by oxidative stress, transforming growth factor-β, and tumor necrosis factor (TNF)-α. The suppressive effect of TNF-α on KLF15 expression was mediated by TNF receptor-1 and nuclear factor-κB. Overexpression of KLF15 in mesangial and HEK293 cells significantly decreased fibronectin and type IV collagen mRNA levels. Furthermore, KLF15 knockout mice developed glomerulosclerosis following uninephrectomy. Thus, KLF15 may be an antifibrotic factor in the kidney, and its decreased expression may contribute to the progression of kidney disease.
Department of Medicine, Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
Xiang
X
Gao
Lianghu
L
Huang
Fabrizio
F
Grosjean
Vittoria
V
Esposito
Jianxiang
J
Wu
Lili
L
Fu
Huimin
H
Hu
Jiangming
J
Tan
Cijian
C
He
Susan
S
Gray
Mukesh K
MK
Jain
Feng
F
Zheng
Changlin
C
Mei
D000818:Animals; D002908:Chronic Disease; D018753:Diet, Protein-Restricted; D019587:Dietary Supplements; D016326:Extracellular Matrix Proteins / Q000235:genetics; D007651:Keto Acids / Q000008:administration & dosage*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000178:diet therapy*; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D009392:Nephrectomy; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016326:Extracellular Matrix Proteins; D007651:Keto Acids; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha
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