Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2
Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonuc...
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| Veröffentlicht in: | American journal of physiology. Renal physiology 2015-02, Vol.308 (4), p.F349-F357 |
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| creator | Ravichandran, Kameswaran Ozkok, Abdullah Wang, Qian Mullick, Adam E Edelstein, Charles L |
| description | Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney. |
| doi_str_mv | 10.1152/ajprenal.00478.2014 |
| format | Article |
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Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney.</description><identifier>ISSN: 1931-857X</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.00478.2014</identifier><identifier>PMID: 25537744</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Angiotensinogen - genetics ; Angiotensinogen - metabolism ; Animals ; Blood Urea Nitrogen ; CD36 Antigens - genetics ; CD36 Antigens - metabolism ; Cells, Cultured ; Chemokine CXCL1 - metabolism ; Cysts ; Cytokines ; Disease Models, Animal ; Down-Regulation ; Female ; Fibrosis ; Genetic Therapy - methods ; Interleukin-12 - metabolism ; Kidney - metabolism ; Kidney - pathology ; Kidney - physiopathology ; Kidney diseases ; Male ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mutation ; Oligonucleotides, Antisense - administration & dosage ; Polycystic Kidney, Autosomal Dominant - genetics ; Polycystic Kidney, Autosomal Dominant - metabolism ; Polycystic Kidney, Autosomal Dominant - pathology ; Polycystic Kidney, Autosomal Dominant - physiopathology ; Polycystic Kidney, Autosomal Dominant - therapy ; Proteins ; Recovery of Function ; Ribonucleic acid ; RNA ; RNA, Messenger - metabolism ; Rodents ; Transforming Growth Factor beta - metabolism ; TRPP Cation Channels - genetics ; TRPP Cation Channels - metabolism</subject><ispartof>American journal of physiology. Renal physiology, 2015-02, Vol.308 (4), p.F349-F357</ispartof><rights>Copyright © 2015 the American Physiological Society.</rights><rights>Copyright American Physiological Society Feb 15, 2015</rights><rights>Copyright © 2015 the American Physiological Society 2015 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-ca6807f37872052f07f5f148b876d2d168164e8d27e8f05d5c3e860d999a6b283</citedby><cites>FETCH-LOGICAL-c466t-ca6807f37872052f07f5f148b876d2d168164e8d27e8f05d5c3e860d999a6b283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25537744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ravichandran, Kameswaran</creatorcontrib><creatorcontrib>Ozkok, Abdullah</creatorcontrib><creatorcontrib>Wang, Qian</creatorcontrib><creatorcontrib>Mullick, Adam E</creatorcontrib><creatorcontrib>Edelstein, Charles L</creatorcontrib><title>Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2</title><title>American journal of physiology. Renal physiology</title><addtitle>Am J Physiol Renal Physiol</addtitle><description>Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney.</description><subject>Angiotensinogen - genetics</subject><subject>Angiotensinogen - metabolism</subject><subject>Animals</subject><subject>Blood Urea Nitrogen</subject><subject>CD36 Antigens - genetics</subject><subject>CD36 Antigens - metabolism</subject><subject>Cells, Cultured</subject><subject>Chemokine CXCL1 - metabolism</subject><subject>Cysts</subject><subject>Cytokines</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Genetic Therapy - methods</subject><subject>Interleukin-12 - metabolism</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidney - physiopathology</subject><subject>Kidney diseases</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Mutant Strains</subject><subject>Mutation</subject><subject>Oligonucleotides, Antisense - administration & dosage</subject><subject>Polycystic Kidney, Autosomal Dominant - genetics</subject><subject>Polycystic Kidney, Autosomal Dominant - metabolism</subject><subject>Polycystic Kidney, Autosomal Dominant - pathology</subject><subject>Polycystic Kidney, Autosomal Dominant - physiopathology</subject><subject>Polycystic Kidney, Autosomal Dominant - therapy</subject><subject>Proteins</subject><subject>Recovery of Function</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>TRPP Cation Channels - genetics</subject><subject>TRPP Cation Channels - metabolism</subject><issn>1931-857X</issn><issn>1522-1466</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkktrGzEURofS0qRpf0GhCLrpZly9pdkUQkgfEEgWKXQn5NEdW86M5EqaBP_7ys6DNquudNE9Ouhyv6Z5T_CCEEE_2802QbDjAmOu9IJiwl80x7VDW8KlfFnrjpFWC_XrqHmT8wZjTAglr5sjKgRTivPj5vY0FJ8hZGgncN4WcMiGlY-l3vkQVxCQD2u_9MXHgPIY7zLaxnHX73LxPbrxLsAOueqwGSqKJt8DuvNljSwqNq1gr5zmYg-CClzdOPq2eTXYMcO7h_Ok-fn1_Prse3tx-e3H2elF29cJSttbqbEamNKKYkGHWouBcL3USjrqiNREctCOKtADFk70DLTErus6K5dUs5Pmy713Oy_rfD2EkuxotslPNu1MtN782wl-bVbx1nBGO65lFXx6EKT4e4ZczORzD-NoA8Q5GyKlplwJSf8DFUJRqTCr6Mdn6CbOqe7yQEnGmNZ7Ibun-hRzTjA8_Ztgs4-AeYyAOUTA7CNQX334e-SnN487Z38A16ywvw</recordid><startdate>20150215</startdate><enddate>20150215</enddate><creator>Ravichandran, Kameswaran</creator><creator>Ozkok, Abdullah</creator><creator>Wang, Qian</creator><creator>Mullick, Adam E</creator><creator>Edelstein, Charles L</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>5PM</scope></search><sort><creationdate>20150215</creationdate><title>Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2</title><author>Ravichandran, Kameswaran ; Ozkok, Abdullah ; Wang, Qian ; Mullick, Adam E ; Edelstein, Charles L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-ca6807f37872052f07f5f148b876d2d168164e8d27e8f05d5c3e860d999a6b283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Angiotensinogen - genetics</topic><topic>Angiotensinogen - metabolism</topic><topic>Animals</topic><topic>Blood Urea Nitrogen</topic><topic>CD36 Antigens - genetics</topic><topic>CD36 Antigens - metabolism</topic><topic>Cells, Cultured</topic><topic>Chemokine CXCL1 - metabolism</topic><topic>Cysts</topic><topic>Cytokines</topic><topic>Disease Models, Animal</topic><topic>Down-Regulation</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Genetic Therapy - methods</topic><topic>Interleukin-12 - metabolism</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidney - physiopathology</topic><topic>Kidney diseases</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Mutant Strains</topic><topic>Mutation</topic><topic>Oligonucleotides, Antisense - administration & dosage</topic><topic>Polycystic Kidney, Autosomal Dominant - genetics</topic><topic>Polycystic Kidney, Autosomal Dominant - metabolism</topic><topic>Polycystic Kidney, Autosomal Dominant - pathology</topic><topic>Polycystic Kidney, Autosomal Dominant - physiopathology</topic><topic>Polycystic Kidney, Autosomal Dominant - therapy</topic><topic>Proteins</topic><topic>Recovery of Function</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>TRPP Cation Channels - genetics</topic><topic>TRPP Cation Channels - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ravichandran, Kameswaran</creatorcontrib><creatorcontrib>Ozkok, Abdullah</creatorcontrib><creatorcontrib>Wang, Qian</creatorcontrib><creatorcontrib>Mullick, Adam E</creatorcontrib><creatorcontrib>Edelstein, Charles L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology. Renal physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ravichandran, Kameswaran</au><au>Ozkok, Abdullah</au><au>Wang, Qian</au><au>Mullick, Adam E</au><au>Edelstein, Charles L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2</atitle><jtitle>American journal of physiology. Renal physiology</jtitle><addtitle>Am J Physiol Renal Physiol</addtitle><date>2015-02-15</date><risdate>2015</risdate><volume>308</volume><issue>4</issue><spage>F349</spage><epage>F357</epage><pages>F349-F357</pages><issn>1931-857X</issn><eissn>1522-1466</eissn><abstract>Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>25537744</pmid><doi>10.1152/ajprenal.00478.2014</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Angiotensinogen - genetics Angiotensinogen - metabolism Animals Blood Urea Nitrogen CD36 Antigens - genetics CD36 Antigens - metabolism Cells, Cultured Chemokine CXCL1 - metabolism Cysts Cytokines Disease Models, Animal Down-Regulation Female Fibrosis Genetic Therapy - methods Interleukin-12 - metabolism Kidney - metabolism Kidney - pathology Kidney - physiopathology Kidney diseases Male Mice, Inbred C57BL Mice, Mutant Strains Mutation Oligonucleotides, Antisense - administration & dosage Polycystic Kidney, Autosomal Dominant - genetics Polycystic Kidney, Autosomal Dominant - metabolism Polycystic Kidney, Autosomal Dominant - pathology Polycystic Kidney, Autosomal Dominant - physiopathology Polycystic Kidney, Autosomal Dominant - therapy Proteins Recovery of Function Ribonucleic acid RNA RNA, Messenger - metabolism Rodents Transforming Growth Factor beta - metabolism TRPP Cation Channels - genetics TRPP Cation Channels - metabolism |
| title | Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2 |
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