title: Fasudil prevents calcium oxalate crystal deposit and renal fibrogenesis in glyoxylate-induced nephrolithic mice.
abstract: Nephrolithiasis is a common kidney disease and one of the major causes of chronic renal insufficiency. We develop and utilize a glyoxylate induced mouse model of kidney calcium oxalate crystal deposition for studying the pharmacological effects of fasudil, a Rho associated protein kinase (ROCK) specific inhibitor, on the kidney injury and fibrosis caused by calcium oxalate crystallization and deposition. Glyoxylate was administrated intraperitoneally to C57BL/6J mice for five consecutive days to establish a mouse model of kidney calcium oxalate crystal formation and deposition. The results showed that the protein expression levels of E-cad and Pan-ck were lower, and the protein expression levels of α-SMA and Vim were higher, in the kidney tissue of the glyoxylate induced model mice compared with the control mice. The changes in protein expression were weakened when the animals were pretreated with fasudil before glyoxylate administration. Expression of ROCK, PAI-1, and p-Smad proteins in the kidney tissue increased in response to glyoxylate treatment, and the increase was eased when the animals were pretreated with fasudil. Expression of Smad2 and Smad3 in the kidney tissue remained unchanged after glyoxylate administration. Cell apoptosis and proliferation in the kidney cortex and medulla were enhanced in response to the glyoxylate induced calcium oxalate crystal formation and deposition, and fasudil pre-treatment was able to attenuate the enhancement. The results suggest that Fasudil reduces the glyoxylate induced kidney calcium crystal formation and deposition and slows down the kidney fibrogenesis caused by calcium crystal deposition. The possible mechanism may be related the regulatory effects on Rho/ROCK signal transduction and epithelial-mesenchymal transition (EMT).
authors.affiliation: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Jiarong
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China. Electronic address: drguozhiyong@163.com.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Guo
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000199:Actins / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000096:biosynthesis; D002129:Calcium Oxalate / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003460:Crystallization; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy* / Q000517:prevention & control; D006038:Glyoxylates; D007668:Kidney / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053040:Nephrolithiasis / Q000188:drug therapy* / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058258:Serpin E2 / Q000096:biosynthesis; D051899:Smad2 Protein / Q000096:biosynthesis; D051900:Smad3 Protein / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000199:Actins; D015820:Cadherins; D006038:Glyoxylates; D047428:Protein Kinase Inhibitors; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C544013:alpha-smooth muscle actin, mouse; D002129:Calcium Oxalate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C031150:glyoxylic acid; C049347:fasudil
keywords: Calcium oxalate; Epithelial–mesenchymal transition; Fasudil; Fibrosis; Smad