Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt
Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California Submitted 18 October 2007 ; accepted in final form 13 June 2008 Heightened sensitivity of the diabetic proximal tubule to dietary salt leads t...
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| Veröffentlicht in: | American Journal of Physiology - Renal Physiology 2008-10, Vol.295 (4), p.F995-F1002 |
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| container_title | American Journal of Physiology - Renal Physiology |
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| creator | Miracle, Cynthia M Rieg, Timo Mansoury, Hadi Vallon, Volker Thomson, Scott C |
| description | Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California
Submitted 18 October 2007
; accepted in final form 13 June 2008
Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg·kg –1 ·day –1 ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption ( J prox ) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed J prox independent of SNGFR. Suppression of J prox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.
diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance
Address for reprint requests and other correspondence: S. Thomson, Division of Nephrology-Hypertension, 3350 La Jolla Village Drive 9151, San Diego, CA 92161 |
| doi_str_mv | 10.1152/ajprenal.00491.2007 |
| format | Article |
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Submitted 18 October 2007
; accepted in final form 13 June 2008
Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg·kg –1 ·day –1 ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption ( J prox ) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed J prox independent of SNGFR. Suppression of J prox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.
diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance
Address for reprint requests and other correspondence: S. Thomson, Division of Nephrology-Hypertension, 3350 La Jolla Village Drive 9151, San Diego, CA 92161</description><identifier>ISSN: 0363-6127</identifier><identifier>ISSN: 1931-857X</identifier><identifier>EISSN: 2161-1157</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.00491.2007</identifier><identifier>PMID: 18562630</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Blood Glucose - metabolism ; Blood Pressure - physiology ; Diabetes ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - pathology ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - pathology ; Eflornithine - pharmacology ; Enzyme Inhibitors - pharmacology ; Feedback, Physiological - drug effects ; Feedback, Physiological - physiology ; Glomerular Filtration Rate - physiology ; Kidney Tubules, Proximal - drug effects ; Kidney Tubules, Proximal - enzymology ; Kidney Tubules, Proximal - pathology ; Kidneys ; Male ; Models, Biological ; Nephrology ; Organ Size ; Ornithine Decarboxylase - metabolism ; Ornithine Decarboxylase Inhibitors ; Rats ; Rats, Wistar ; Rodents ; Sodium Chloride, Dietary - pharmacology ; Studies ; Urine</subject><ispartof>American Journal of Physiology - Renal Physiology, 2008-10, Vol.295 (4), p.F995-F1002</ispartof><rights>Copyright American Physiological Society Oct 2008</rights><rights>Copyright © 2008, American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c520t-a79923cedacd963d4f6382511679847a32d67829f466a8392bda4805d7b67f3c3</citedby><cites>FETCH-LOGICAL-c520t-a79923cedacd963d4f6382511679847a32d67829f466a8392bda4805d7b67f3c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18562630$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miracle, Cynthia M</creatorcontrib><creatorcontrib>Rieg, Timo</creatorcontrib><creatorcontrib>Mansoury, Hadi</creatorcontrib><creatorcontrib>Vallon, Volker</creatorcontrib><creatorcontrib>Thomson, Scott C</creatorcontrib><title>Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt</title><title>American Journal of Physiology - Renal Physiology</title><addtitle>Am J Physiol Renal Physiol</addtitle><description>Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California
Submitted 18 October 2007
; accepted in final form 13 June 2008
Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg·kg –1 ·day –1 ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption ( J prox ) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed J prox independent of SNGFR. Suppression of J prox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.
diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance
Address for reprint requests and other correspondence: S. Thomson, Division of Nephrology-Hypertension, 3350 La Jolla Village Drive 9151, San Diego, CA 92161</description><subject>Animals</subject><subject>Blood Glucose - metabolism</subject><subject>Blood Pressure - physiology</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetic Nephropathies - metabolism</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Eflornithine - pharmacology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Feedback, Physiological - drug effects</subject><subject>Feedback, Physiological - physiology</subject><subject>Glomerular Filtration Rate - physiology</subject><subject>Kidney Tubules, Proximal - drug effects</subject><subject>Kidney Tubules, Proximal - enzymology</subject><subject>Kidney Tubules, Proximal - pathology</subject><subject>Kidneys</subject><subject>Male</subject><subject>Models, Biological</subject><subject>Nephrology</subject><subject>Organ Size</subject><subject>Ornithine Decarboxylase - metabolism</subject><subject>Ornithine Decarboxylase Inhibitors</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Rodents</subject><subject>Sodium Chloride, Dietary - pharmacology</subject><subject>Studies</subject><subject>Urine</subject><issn>0363-6127</issn><issn>1931-857X</issn><issn>2161-1157</issn><issn>1522-1466</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU2P0zAYhCMEYrsLvwAJWRy4tfgjdmIOSGhFAWmlvSxny4nfNK7cONhOt_n3eLelC0icfJhnRuN3iuINwStCOP2gt2OAQbsVxqUkK4px9axYUCLIMuvV82KBmWBLQWh1UVzGuMWYUlGLl8UFqbmgguFFsb8Ng029HQAZaHVo_GF2OgKyQ28bm3xA4OzODjpBRP08QggQRz9Eu4cBYkS-Q6kHBDq4GRmrG0i2RWPwB7vTDqWpmRyg5LMGSYcZRe3Sq-JFp12E16f3qvix_nJ3_W15c_v1-_Xnm2XLKU5LXUlJWQtGt0YKZspOsJpyQkQl67LSjBpR1VR2pRC6ZpI2Rpc15qZqRNWxll0Vn46549TswLQwpKCdGkPuFmbltVV_K4Pt1cbvFeWVyJfMAe9PAcH_nCAmtbOxBef0AH6KSkhRCs5pBt_9A279FPI8UVGGsZSc1hliR6gNPsYA3bkJwephVPV7VPU4qnoYNbve_vmJJ89pxQx8PAK93fT3NoAa-zla7_xmVuvJuTs4pHM0lVyVap0bqdF02bz6v_lc58nEfgEoV8l4</recordid><startdate>20081001</startdate><enddate>20081001</enddate><creator>Miracle, Cynthia M</creator><creator>Rieg, Timo</creator><creator>Mansoury, Hadi</creator><creator>Vallon, Volker</creator><creator>Thomson, Scott C</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>5PM</scope></search><sort><creationdate>20081001</creationdate><title>Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt</title><author>Miracle, Cynthia M ; Rieg, Timo ; Mansoury, Hadi ; Vallon, Volker ; Thomson, Scott C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c520t-a79923cedacd963d4f6382511679847a32d67829f466a8392bda4805d7b67f3c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Blood Glucose - metabolism</topic><topic>Blood Pressure - physiology</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetic Nephropathies - metabolism</topic><topic>Diabetic Nephropathies - pathology</topic><topic>Eflornithine - pharmacology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Feedback, Physiological - drug effects</topic><topic>Feedback, Physiological - physiology</topic><topic>Glomerular Filtration Rate - physiology</topic><topic>Kidney Tubules, Proximal - drug effects</topic><topic>Kidney Tubules, Proximal - enzymology</topic><topic>Kidney Tubules, Proximal - pathology</topic><topic>Kidneys</topic><topic>Male</topic><topic>Models, Biological</topic><topic>Nephrology</topic><topic>Organ Size</topic><topic>Ornithine Decarboxylase - metabolism</topic><topic>Ornithine Decarboxylase Inhibitors</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Rodents</topic><topic>Sodium Chloride, Dietary - pharmacology</topic><topic>Studies</topic><topic>Urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miracle, Cynthia M</creatorcontrib><creatorcontrib>Rieg, Timo</creatorcontrib><creatorcontrib>Mansoury, Hadi</creatorcontrib><creatorcontrib>Vallon, Volker</creatorcontrib><creatorcontrib>Thomson, Scott C</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>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>Miracle, Cynthia M</au><au>Rieg, Timo</au><au>Mansoury, Hadi</au><au>Vallon, Volker</au><au>Thomson, Scott C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt</atitle><jtitle>American Journal of Physiology - Renal Physiology</jtitle><addtitle>Am J Physiol Renal Physiol</addtitle><date>2008-10-01</date><risdate>2008</risdate><volume>295</volume><issue>4</issue><spage>F995</spage><epage>F1002</epage><pages>F995-F1002</pages><issn>0363-6127</issn><issn>1931-857X</issn><eissn>2161-1157</eissn><eissn>1522-1466</eissn><abstract>Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California
Submitted 18 October 2007
; accepted in final form 13 June 2008
Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg·kg –1 ·day –1 ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption ( J prox ) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed J prox independent of SNGFR. Suppression of J prox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.
diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance
Address for reprint requests and other correspondence: S. Thomson, Division of Nephrology-Hypertension, 3350 La Jolla Village Drive 9151, San Diego, CA 92161</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>18562630</pmid><doi>10.1152/ajprenal.00491.2007</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | American Journal of Physiology - Renal Physiology, 2008-10, Vol.295 (4), p.F995-F1002 |
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| source | MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Blood Glucose - metabolism Blood Pressure - physiology Diabetes Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - pathology Diabetic Nephropathies - metabolism Diabetic Nephropathies - pathology Eflornithine - pharmacology Enzyme Inhibitors - pharmacology Feedback, Physiological - drug effects Feedback, Physiological - physiology Glomerular Filtration Rate - physiology Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - enzymology Kidney Tubules, Proximal - pathology Kidneys Male Models, Biological Nephrology Organ Size Ornithine Decarboxylase - metabolism Ornithine Decarboxylase Inhibitors Rats Rats, Wistar Rodents Sodium Chloride, Dietary - pharmacology Studies Urine |
| title | Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt |
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