title: Sodium restriction potentiates the renoprotective effects of combined vitamin D receptor activation and angiotensin-converting enzyme inhibition in established proteinuric nephropathy.
abstract: BACKGROUND
  Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodium intake.
  
  
  METHODS
  Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alpha-smooth muscle actin (α-SMA) at the end of the treatment.
  
  
  RESULTS
  Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of α-SMA during the low-sodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes.
  
  
  CONCLUSIONS
  The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD.
authors: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Katarina
authors: K
authors: Mirkovic
authors: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Anne-Roos S
authors: AS
authors: Frenay
authors: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Jacob
authors: J
authors: van den Born
authors: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Harry
authors: H
authors: van Goor
authors: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Gerjan
authors: G
authors: Navis
authors: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Martin H
authors: MH
authors: de Borst
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D004039:Diet, Sodium-Restricted; D004872:Ergocalciferols / Q000494:pharmacology; D015433:Glomerulonephritis, Membranous / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry*; D011507:Proteinuria / Q000150:complications*; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D012982:Sodium, Dietary / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; D017673:Sodium Chloride, Dietary; D012982:Sodium, Dietary; C084656:paricalcitol; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A
keywords: chronic kidney disease; proteinuria; renin–angiotensin–aldosterone system; sodium; vitamin D