title: Targeting reduction of proteinuria in glomerulonephritis: Maximizing the antifibrotic effect of valsartan by protecting podocytes.
abstract: Although angiotensin (Ang) II blockade has become a standard antifibrotic therapy in kidney disease, the therapeutic efficacy of Ang II blockade is yet to be optimized. Considering the prognostic impact of proteinuria reduction, we hypothesized that titration of Ang II blockade for optimal anti-proteinuric effect would improve renoprotection. One day after induction of Thy 1.1 glomeruonephritis, rats were treated with increasing doses of the Ang II receptor blocker valsartan in drinking water. Six days after disease induction, the therapeutic effect on proteinuria, podocyte injury and glomerular fibrosis was evaluated. Increasing doses of valsartan resulted in increasing reduction of proteinuria. The maximally effective dose of valsartan was determined to be 1000 mg/l, which reduced proteinuria by 80% and maximally reduced glomerular matrix expansion, fibronectin, collagen I and collagen III staining and glomerular mRNAs for TGFß1, PAI-1, FN and collagen I. Notably, valsartan given at this dose prevented podocyte dysfunction by preserving expression of podocin and nephrin and the counter-regulating molecule B7-1 that is involved in podocyte injury. These results support the hypothesis that higher doses of valsartan are required to optimize proteinuria reduction and glomerulosclerosis amelioration. Further, the optimal dose of valsartan also provides an additional therapeutic effect by preventing podocyte dysfunction.
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Gu
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, USA.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Noble
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Border
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, USA.
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Fibrosis Research Laboratory, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, USA yufeng.huang@hsc.utah.edu.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Huang
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D005921:Glomerulonephritis / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D013777:Tetrazoles; C113267:nephrin; D000068756:Valsartan; D014633:Valine