title: Mesenchymal Stromal Cells Prevent Renal Fibrosis in a Rat Model of Unilateral Ureteral Obstruction by Suppressing the Renin-Angiotensin System via HuR.
abstract: We studied Mesenchymal Stromal Cells (MSC) effects in experimental Unilateral Ureteral Obstruction (UUO), a fibrogenic renal disease. Rats were divided in 5 groups: sham, UUO, MSC treated-UUO, ACEi treated-UUO, MSC+ACEi treated- UUO. Data were collected at 1, 7, 21 days. UUO induced monocyte renal infiltration, tubular cell apoptosis, tubular atrophy, interstitial fibrosis and overexpression of TGFβ, Renin mRNA (RENmRNA), increase of Renin, Angiotensin II (AII) and aldosterone serum levels. Both lisinopril (ACEi) and MSC treatment prevented monocyte infiltration, reduced tubular cell apoptosis, renal fibrosis and TGFβ expression. Combined therapy provided a further suppression of monocyte infiltration and tubular injury. Lisinopril alone caused a rebound activation of Renin-Angiotensin System (RAS), while MSC suppressed RENmRNA and Renin synthesis and induced a decrease of AII and aldosterone serum levels. Furthermore, in in-vitro and in-vivo experiments, MSC inhibit Human antigen R (HuR) trascription, an enhancer of RENmRNA stability by IL10 release. In conclusion, we demonstrate that in UUO MSC prevent fibrosis, by decreasing HuR-dependent RENmRNA stability. Our findings give a clue to understand the molecular mechanism through which MSC may prevent fibrosis in a wide and heterogeneous number of diseases that share RAS activation as common upstream pathogenic mechanism.
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Marilena
authors: M
authors: Gregorini
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Valeria
authors: V
authors: Corradetti
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Chiara
authors: C
authors: Rocca
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Eleonora Francesca
authors: EF
authors: Pattonieri
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Teresa
authors: T
authors: Valsania
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Samantha
authors: S
authors: Milanesi
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Nicoletta
authors: N
authors: Serpieri
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Giulia
authors: G
authors: Bedino
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Pasquale
authors: P
authors: Esposito
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Carmelo
authors: C
authors: Libetta
authors: Laboratory of Transplant Immunology/Cell Factory Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors: Maria Antonietta
authors: MA
authors: Avanzini
authors: Laboratory of Transplant Immunology/Cell Factory Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors: Melissa
authors: M
authors: Mantelli
authors: Laboratory of Transplant Immunology/Cell Factory Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors: Daniela
authors: D
authors: Ingo
authors: Clinical Chemistry Laboratory Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors: Sabrina
authors: S
authors: Peressini
authors: Clinical Chemistry Laboratory Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors: Riccardo
authors: R
authors: Albertini
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Antonio
authors: A
authors: Dal Canton
authors: Unit of Nephrology, Dialysis, Transplantation, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Teresa
authors: T
authors: Rampino
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D000067780:ELAV-Like Protein 1 / Q000502:physiology*; D005355:Fibrosis / Q000503:physiopathology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology*; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000096:biosynthesis; D012084:Renin-Angiotensin System; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000503:physiopathology* / Q000628:therapy
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000593998:Elavl1 protein, rat; C508609:IL10 protein, human; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D000450:Aldosterone; D012083:Renin