Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney
Abstract Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined...
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| Veröffentlicht in: | Kidney & blood pressure research 2023-01, Vol.48 (1), p.326-337 |
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| creator | Takenaka, Tsuneo Hasan, Arif Marumo, Takeshi Inoue, Tsutomu Miyazaki, Takashi Suzuki, Hiromichi Kurosaki, Yoshifumi Ishii, Naohito Nishiyama, Akira Hayashi, Matsuhiko |
| description | Abstract
Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (−43%), systolic blood pressure (−16%), fibroblast growth factor (FGF) 23 (−51%) and serum phosphate levels (−19%), renal angiotensin II concentration (−43%), fibrosis index (−70%), renal expressions of collagen I (−55%), and transforming growth factor β (−59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). Conclusion: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney. |
| doi_str_mv | 10.1159/000530469 |
| format | Article |
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Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (−43%), systolic blood pressure (−16%), fibroblast growth factor (FGF) 23 (−51%) and serum phosphate levels (−19%), renal angiotensin II concentration (−43%), fibrosis index (−70%), renal expressions of collagen I (−55%), and transforming growth factor β (−59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). Conclusion: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.</description><identifier>ISSN: 1420-4096</identifier><identifier>EISSN: 1423-0143</identifier><identifier>DOI: 10.1159/000530469</identifier><identifier>PMID: 37019097</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Angiotensin ; Angiotensin II ; Animals ; Antibiotics ; Apoptosis ; Blood pressure ; Bone morphogenetic proteins ; Collagen (type I) ; Enzyme-linked immunosorbent assay ; Enzymes ; Excretion ; Fibroblast growth factor 23 ; Fibroblasts ; Fibrosis ; Glomerular filtration rate ; Growth factors ; Histology ; Impact damage ; In vivo methods and tests ; Insulin-like growth factors ; Kidney diseases ; Kidneys ; Klotho protein ; Nephrectomy ; Proteins ; Radioimmunoassay ; Renal function ; Renin ; Research Article ; Superoxide dismutase ; Supplements ; Transforming growth factor-b ; Urine ; Veins & arteries</subject><ispartof>Kidney & blood pressure research, 2023-01, Vol.48 (1), p.326-337</ispartof><rights>2023 The Author(s). Published by S. Karger AG, Basel</rights><rights>2023 The Author(s). Published by S. Karger AG, Basel.</rights><rights>2023 The Author(s). Published by S. Karger AG, Basel. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at: https://uk.sagepub.com/en-gb/eur/reusing-open-access-and-sage-choice-content</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-47e797d0c369c8c15ae03a9fb367ada8a0cf2125266721c220e7f71960463b3b3</citedby><cites>FETCH-LOGICAL-c529t-47e797d0c369c8c15ae03a9fb367ada8a0cf2125266721c220e7f71960463b3b3</cites><orcidid>0000-0002-3383-1340 ; 0000-0001-5971-820X ; 0000-0002-1613-1887</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,2102,27635,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37019097$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takenaka, Tsuneo</creatorcontrib><creatorcontrib>Hasan, Arif</creatorcontrib><creatorcontrib>Marumo, Takeshi</creatorcontrib><creatorcontrib>Inoue, Tsutomu</creatorcontrib><creatorcontrib>Miyazaki, Takashi</creatorcontrib><creatorcontrib>Suzuki, Hiromichi</creatorcontrib><creatorcontrib>Kurosaki, Yoshifumi</creatorcontrib><creatorcontrib>Ishii, Naohito</creatorcontrib><creatorcontrib>Nishiyama, Akira</creatorcontrib><creatorcontrib>Hayashi, Matsuhiko</creatorcontrib><title>Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney</title><title>Kidney & blood pressure research</title><addtitle>Kidney Blood Press Res</addtitle><description>Abstract
Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (−43%), systolic blood pressure (−16%), fibroblast growth factor (FGF) 23 (−51%) and serum phosphate levels (−19%), renal angiotensin II concentration (−43%), fibrosis index (−70%), renal expressions of collagen I (−55%), and transforming growth factor β (−59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). Conclusion: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.</description><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Apoptosis</subject><subject>Blood pressure</subject><subject>Bone morphogenetic proteins</subject><subject>Collagen (type I)</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Enzymes</subject><subject>Excretion</subject><subject>Fibroblast growth factor 23</subject><subject>Fibroblasts</subject><subject>Fibrosis</subject><subject>Glomerular filtration rate</subject><subject>Growth factors</subject><subject>Histology</subject><subject>Impact damage</subject><subject>In vivo methods and tests</subject><subject>Insulin-like growth factors</subject><subject>Kidney diseases</subject><subject>Kidneys</subject><subject>Klotho protein</subject><subject>Nephrectomy</subject><subject>Proteins</subject><subject>Radioimmunoassay</subject><subject>Renal function</subject><subject>Renin</subject><subject>Research Article</subject><subject>Superoxide dismutase</subject><subject>Supplements</subject><subject>Transforming growth factor-b</subject><subject>Urine</subject><subject>Veins & arteries</subject><issn>1420-4096</issn><issn>1423-0143</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>M--</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DOA</sourceid><recordid>eNptkc-L1TAQx4so7rp68C5S8KKH6iRpk-a4rq4-3oKw6lFCmk7XPNukJqnw_nvzfvgEkRwyzHzy_U5miuIpgdeENPINADQMai7vFeekpqwCUrP7-xiqGiQ_Kx7FuNlhAPRhccYEEAlSnBff1qNP3335eZnnESd0SSfrXXmLvzBEjDlweizfbeOwOLMvadeXK5dyOdlkc_HadsFHG0u7ezc57VK5tr3D7ePiwaDHiE-O90Xx9fr9l6uP1c2nD6ury5vKNFSmqhYopOjBMC5Na0ijEZiWQ8e40L1uNZiBEtpQzgUlhlJAMQgief4z6_K5KFYH3d7rjZqDnXTYKq-t2id8uFM6JGtGVF0nZN31LVDkteBSQt90WlMEnb0JZq2XB605-J8LxqQmGw2Oo3bol6hobpXUvKVtRl_8g278EvK8MiWBC85Y22Tq1YEyeUox4HBqkIDa7U-d9pfZ50fFpZuwP5F_FvbX8ocOdxhOwPrt7UFCzf2QqWf_pY4uvwFLNKjD</recordid><startdate>20230101</startdate><enddate>20230101</enddate><creator>Takenaka, Tsuneo</creator><creator>Hasan, Arif</creator><creator>Marumo, Takeshi</creator><creator>Inoue, Tsutomu</creator><creator>Miyazaki, Takashi</creator><creator>Suzuki, Hiromichi</creator><creator>Kurosaki, Yoshifumi</creator><creator>Ishii, Naohito</creator><creator>Nishiyama, Akira</creator><creator>Hayashi, Matsuhiko</creator><general>S. 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Hasan, Arif ; Marumo, Takeshi ; Inoue, Tsutomu ; Miyazaki, Takashi ; Suzuki, Hiromichi ; Kurosaki, Yoshifumi ; Ishii, Naohito ; Nishiyama, Akira ; Hayashi, Matsuhiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-47e797d0c369c8c15ae03a9fb367ada8a0cf2125266721c220e7f71960463b3b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Apoptosis</topic><topic>Blood pressure</topic><topic>Bone morphogenetic proteins</topic><topic>Collagen (type I)</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Enzymes</topic><topic>Excretion</topic><topic>Fibroblast growth factor 23</topic><topic>Fibroblasts</topic><topic>Fibrosis</topic><topic>Glomerular filtration rate</topic><topic>Growth factors</topic><topic>Histology</topic><topic>Impact damage</topic><topic>In vivo methods and tests</topic><topic>Insulin-like growth factors</topic><topic>Kidney diseases</topic><topic>Kidneys</topic><topic>Klotho protein</topic><topic>Nephrectomy</topic><topic>Proteins</topic><topic>Radioimmunoassay</topic><topic>Renal function</topic><topic>Renin</topic><topic>Research Article</topic><topic>Superoxide dismutase</topic><topic>Supplements</topic><topic>Transforming growth factor-b</topic><topic>Urine</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takenaka, Tsuneo</creatorcontrib><creatorcontrib>Hasan, Arif</creatorcontrib><creatorcontrib>Marumo, Takeshi</creatorcontrib><creatorcontrib>Inoue, Tsutomu</creatorcontrib><creatorcontrib>Miyazaki, Takashi</creatorcontrib><creatorcontrib>Suzuki, Hiromichi</creatorcontrib><creatorcontrib>Kurosaki, Yoshifumi</creatorcontrib><creatorcontrib>Ishii, Naohito</creatorcontrib><creatorcontrib>Nishiyama, Akira</creatorcontrib><creatorcontrib>Hayashi, Matsuhiko</creatorcontrib><collection>Karger Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Kidney & blood pressure research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takenaka, Tsuneo</au><au>Hasan, Arif</au><au>Marumo, Takeshi</au><au>Inoue, Tsutomu</au><au>Miyazaki, Takashi</au><au>Suzuki, Hiromichi</au><au>Kurosaki, Yoshifumi</au><au>Ishii, Naohito</au><au>Nishiyama, Akira</au><au>Hayashi, Matsuhiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney</atitle><jtitle>Kidney & blood pressure research</jtitle><addtitle>Kidney Blood Press Res</addtitle><date>2023-01-01</date><risdate>2023</risdate><volume>48</volume><issue>1</issue><spage>326</spage><epage>337</epage><pages>326-337</pages><issn>1420-4096</issn><eissn>1423-0143</eissn><abstract>Abstract
Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (−43%), systolic blood pressure (−16%), fibroblast growth factor (FGF) 23 (−51%) and serum phosphate levels (−19%), renal angiotensin II concentration (−43%), fibrosis index (−70%), renal expressions of collagen I (−55%), and transforming growth factor β (−59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). Conclusion: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>37019097</pmid><doi>10.1159/000530469</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-3383-1340</orcidid><orcidid>https://orcid.org/0000-0001-5971-820X</orcidid><orcidid>https://orcid.org/0000-0002-1613-1887</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Angiotensin Angiotensin II Animals Antibiotics Apoptosis Blood pressure Bone morphogenetic proteins Collagen (type I) Enzyme-linked immunosorbent assay Enzymes Excretion Fibroblast growth factor 23 Fibroblasts Fibrosis Glomerular filtration rate Growth factors Histology Impact damage In vivo methods and tests Insulin-like growth factors Kidney diseases Kidneys Klotho protein Nephrectomy Proteins Radioimmunoassay Renal function Renin Research Article Superoxide dismutase Supplements Transforming growth factor-b Urine Veins & arteries |
| title | Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney |
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