title: Regression of Renal Disease by Angiotensin II Antagonism Is Caused by Regeneration of Kidney Vasculature.
abstract: Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-β and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin-angiotensin system regenerated kidney vasculature and normalized Tgf-β and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy; Department of Industrial Engineering, Bergamo University, Dalmine (Bergamo), Italy; and andrea.remuzzi@marionegri.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Remuzzi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Sangalli
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Macconi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Susanna
authors.initials: S
authors.lastname: Tomasoni
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Irene
authors.initials: I
authors.lastname: Cattaneo
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Barbara
authors.initials: B
authors.lastname: Bonandrini
authors.affiliation: Department of Industrial Engineering, Bergamo University, Dalmine (Bergamo), Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Bresciani
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy;
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000199:Actins / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology; D019332:Endothelin-1 / Q000235:genetics; D015870:Gene Expression; D007678:Kidney Glomerulus / Q000098:blood supply*; D008855:Microscopy, Electron, Scanning; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy*; D012084:Renin-Angiotensin System / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D000199:Actins; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D051267:NF-E2-Related Factor 2; D016212:Transforming Growth Factor beta; C495637:Nfe2l2 protein, rat; C498862:Acta2 protein, rat
keywords: angiotensin–converting enzyme inhibitors; renal progression; vascular disease