Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating MIR-22 and BMP7

Riccardo Pofi, Daniela Fiore, Rita De Gaetano, Giuseppe Panio, Daniele Gianfrilli, Carlotta Pozza, Federica Barbagallo, Yang Kevin Xiang, Konstantinos Giannakakis, Susanna Morano, Andrea Lenzi, Fabio Naro, Andrea M. Isidori, Mary Anna Venneri

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number44584
JournalScientific Reports
Volume7
DOIs
StatePublished - Mar 15 2017

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Bone Morphogenetic Protein 7
Type 5 Cyclic Nucleotide Phosphodiesterases
Diabetic Nephropathies
Hemodynamics
Kidney
Phosphodiesterase 5 Inhibitors
Blood Vessels
Urokinase Plasminogen Activator Receptors
Pericytes
Diabetes Complications
Microcirculation
Glomerular Filtration Rate
Chronic Kidney Failure
Endothelium
Albumins
Creatinine
Homeostasis
Down-Regulation
Perfusion
Cell Count

ASJC Scopus subject areas

  • General

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Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating MIR-22 and BMP7. / Pofi, Riccardo; Fiore, Daniela; De Gaetano, Rita; Panio, Giuseppe; Gianfrilli, Daniele; Pozza, Carlotta; Barbagallo, Federica; Xiang, Yang Kevin; Giannakakis, Konstantinos; Morano, Susanna; Lenzi, Andrea; Naro, Fabio; Isidori, Andrea M.; Venneri, Mary Anna.

In: Scientific Reports, Vol. 7, 44584, 15.03.2017.

Research output: Contribution to journalArticle

Pofi, R, Fiore, D, De Gaetano, R, Panio, G, Gianfrilli, D, Pozza, C, Barbagallo, F, Xiang, YK, Giannakakis, K, Morano, S, Lenzi, A, Naro, F, Isidori, AM & Venneri, MA 2017, 'Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating MIR-22 and BMP7', Scientific Reports, vol. 7, 44584. https://doi.org/10.1038/srep44584
Pofi, Riccardo ; Fiore, Daniela ; De Gaetano, Rita ; Panio, Giuseppe ; Gianfrilli, Daniele ; Pozza, Carlotta ; Barbagallo, Federica ; Xiang, Yang Kevin ; Giannakakis, Konstantinos ; Morano, Susanna ; Lenzi, Andrea ; Naro, Fabio ; Isidori, Andrea M. ; Venneri, Mary Anna. / Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating MIR-22 and BMP7. In: Scientific Reports. 2017 ; Vol. 7.
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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.",
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AU - Panio, Giuseppe

AU - Gianfrilli, Daniele

AU - Pozza, Carlotta

AU - Barbagallo, Federica

AU - Xiang, Yang Kevin

AU - Giannakakis, Konstantinos

AU - Morano, Susanna

AU - Lenzi, Andrea

AU - Naro, Fabio

AU - Isidori, Andrea M.

AU - Venneri, Mary Anna

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