title: Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy.
abstract: Local inflammation is thought to contribute to the progression of diabetic nephropathy. The vitamin D receptor (VDR) activator paricalcitol has an antiproteinuric effect in human diabetic nephropathy at high doses. We have explored potential anti-inflammatory effects of VDR activator doses that do not modulate proteinuria in an experimental model of diabetic nephropathy to gain insights into potential benefits of VDR activators in those patients whose proteinuria is not decreased by this therapy. The effect of calcitriol and paricalcitol on renal function, albuminuria, and renal inflammation was explored in a rat experimental model of diabetes induced by streptozotocin. Modulation of the expression of mediators of inflammation by these drugs was explored in cultured podocytes. At the doses used, neither calcitriol nor paricalcitol significantly modified renal function or reduced albuminuria in experimental diabetes. However, both drugs reduced the total kidney mRNA expression of IL-6, monocyte chemoattractant protein (MCP)-1, and IL-18. Immunohistochemistry showed that calcitriol and paricalcitol reduced MCP-1 and IL-6 in podocytes and tubular cells as well as glomerular infiltration by macrophages, glomerular cell NF-κB activation, apoptosis, and extracellular matrix deposition. In cultured podocytes, paricalcitol and calcitriol at concentrations in the physiological and clinically significant range prevented the increase in MCP-1, IL-6, renin, and fibronectin mRNA expression and the secretion of MCP-1 to the culture media induced by high glucose. In conclusion, in experimental diabetic nephropathy VDR activation has local renal anti-inflammatory effects that can be observed even when proteinuria is not decreased. This may be ascribed to decreased inflammatory responses of intrinsic renal cells, including podocytes, to high glucose.
authors.affiliation: Research Laboratory and Nephrology Department, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, Lleida, Spain.
authors.forename: Maria-Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.forename: Milica
authors.initials: M
authors.lastname: Bozic
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Córdoba-Lanús
authors.forename: Petya
authors.initials: P
authors.lastname: Valcheva
authors.forename: Olga
authors.initials: O
authors.lastname: Gracia
authors.forename: Merce
authors.initials: M
authors.lastname: Ibarz
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernandez
authors.forename: Juan F
authors.initials: JF
authors.lastname: Navarro-Gonzalez
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Valdivielso
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D004872:Ergocalciferols / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*
chemical_list: D050071:Bone Density Conservation Agents; D002120:Calcium Channel Agonists; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C084656:paricalcitol; D002117:Calcitriol; D005947:Glucose