title: Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7.
abstract: Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5is) exert protective effects in DN improving perivascular inflammation. Using a mouse model of diabetic kidney injury we investigated the protective proprieties of PDE5is on renal hemodynamics and the molecular mechanisms involved. PDE5i treatment prevented the development of DN-related hypertension (P < 0.001), the increase of urine albumin creatinine ratio (P < 0.01), the fall in glomerular filtration rate (P < 0.001), and improved renal resistive index (P < 0.001) and kidney microcirculation. Moreover PDE5i attenuated the rise of nephropathy biomarkers, soluble urokinase-type plasminogen activator receptor, suPAR and neutrophil gelatinase-associated lipocalin, NGAL. In treated animals, blood vessel perfusion was improved and vascular leakage reduced, suggesting preserved renal endothelium integrity, as confirmed by higher capillary density, number of CD31+cells and pericyte coverage. Analysis of the mechanisms involved revealed the induction of bone morphogenetic protein-7 (BMP7) expression, a critical regulator of angiogenesis and kidney homeostasis, through a PDE5i-dependent downregulation of miR-22. In conclusion PDE5i slows the progression of DN in mice, improving hemodynamic parameters and vessel integrity. Regulation of miR-22/BMP7, an unknown mechanism of PDE5is in nephrovascular protection, might represent a novel therapeutic option for treatment of diabetic complications.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pofi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fiore
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: De Gaetano
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Panio
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Gianfrilli
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Pozza
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barbagallo
authors.affiliation: Department of Pharmacology, University of California at Davis, California, USA.
authors.forename: Yang Kevin
authors.initials: YK
authors.lastname: Xiang
authors.affiliation: Department of Radiology, Oncology, Radiology and Pathology, Sapienza University of Rome, Italy.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Giannakakis
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Morano
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Mary Anna
authors.initials: MA
authors.lastname: Venneri
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics*; D003404:Creatinine / Q000652:urine; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000187:drug effects / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics
chemical_list: D000418:Albumins; D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D058986:Phosphodiesterase 5 Inhibitors; D055293:Receptors, Urokinase Plasminogen Activator; C525820:bmp7 protein, mouse; D003404:Creatinine; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5