title: Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.
abstract: Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yin
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Ni
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Long
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: You
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Shan-Yan
authors.initials: SY
authors.lastname: Lin
authors.affiliation: 1Division of Nephrology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai 200040,People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000804:Angiotensin II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018753:Diet, Protein-Restricted; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D007651:Keto Acids / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D050527:Mesangial Cells / Q000201:enzymology / Q000378:metabolism; D009392:Nephrectomy / Q000009:adverse effects; D018384:Oxidative Stress; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D040901:Proteomics / Q000379:methods; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System; D014511:Uremia / Q000178:diet therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D000092502:Renin Inhibitors
chemical_list: D000804:Angiotensin II; D007651:Keto Acids; D044140:Receptor, Angiotensin, Type 1; D012083:Renin; D000092502:Renin Inhibitors; C544067:Agtr1a protein, rat
keywords:  AT1R Ang type 1 receptor;  AngII angiotensin II;  CKD chronic kidney diseases;  FN fibronectin;  KA ketoacids;  LPD low-protein diet;  LPD+KA low-protein diet plus ketoacids;  Nx-LPD 6 % low-protein diet;  Nx-LPD+KA 5 % low-protein diet plus 1 % ketoacids;  Nx-NPD 18 % normal-protein diet;  RAS renin–angiotensin system;  TGF-β
                  transforming growth factor-β1; 3/4 Nephrectomised rats; Chronic kidney diseases; Ketoacids; Low-protein diet; Renin–angiotensin system