Treatment with 2,4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific Coq6 Knockout Mice
Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also calle...
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| Veröffentlicht in: | Journal of the American Society of Nephrology Jg. 30; H. 3; S. 393 |
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| Sprache: | Englisch |
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01.03.2019
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| Abstract | Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ
, CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function.
To study
function in podocytes, we generated a podocyte-specific
knockout mouse (
) model and a transient siRNA-based
knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in
knockdown podocytes and control podocytes. We also randomly assigned 5-month-old
mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States.
Abrogation of
in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria).
studies revealed an impaired podocyte migration rate in
knockdown human podocytes. Treating
mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of
mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated
mice, half of which died by 10 months of age.
These findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ
biosynthesis pathway. |
|---|---|
| AbstractList | Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ10, CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function.BACKGROUNDAlthough studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ10, CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function.To study COQ6 function in podocytes, we generated a podocyte-specific Coq6 knockout mouse (Coq6podKO ) model and a transient siRNA-based COQ6 knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in COQ6 knockdown podocytes and control podocytes. We also randomly assigned 5-month-old Coq6podKO mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States.METHODSTo study COQ6 function in podocytes, we generated a podocyte-specific Coq6 knockout mouse (Coq6podKO ) model and a transient siRNA-based COQ6 knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in COQ6 knockdown podocytes and control podocytes. We also randomly assigned 5-month-old Coq6podKO mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States.Abrogation of Coq6 in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria). In vitro studies revealed an impaired podocyte migration rate in COQ6 knockdown human podocytes. Treating Coq6podKO mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of Coq6podKO mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated Coq6podKO mice, half of which died by 10 months of age.RESULTSAbrogation of Coq6 in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria). In vitro studies revealed an impaired podocyte migration rate in COQ6 knockdown human podocytes. Treating Coq6podKO mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of Coq6podKO mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated Coq6podKO mice, half of which died by 10 months of age.These findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ10 biosynthesis pathway.CONCLUSIONSThese findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ10 biosynthesis pathway. Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ , CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function. To study function in podocytes, we generated a podocyte-specific knockout mouse ( ) model and a transient siRNA-based knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in knockdown podocytes and control podocytes. We also randomly assigned 5-month-old mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States. Abrogation of in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria). studies revealed an impaired podocyte migration rate in knockdown human podocytes. Treating mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated mice, half of which died by 10 months of age. These findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ biosynthesis pathway. |
| Author | Airik, Merlin Schueler, Markus Schneider, Ronen Airik, Rannar Hildebrandt, Friedhelm Nakayama, Makiko Widmeier, Eugen Awad, Agape M Wedel, Johannes Schapiro, David Nag, Anish Clarke, Catherine F Ghosh, Chandra C Cho, Jang Hugo, Hannah |
| Author_xml | – sequence: 1 givenname: Eugen surname: Widmeier fullname: Widmeier, Eugen organization: Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany – sequence: 2 givenname: Merlin surname: Airik fullname: Airik, Merlin organization: Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania; and – sequence: 3 givenname: Hannah surname: Hugo fullname: Hugo, Hannah organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 4 givenname: David surname: Schapiro fullname: Schapiro, David organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 5 givenname: Johannes surname: Wedel fullname: Wedel, Johannes organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 6 givenname: Chandra C surname: Ghosh fullname: Ghosh, Chandra C organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 7 givenname: Makiko surname: Nakayama fullname: Nakayama, Makiko organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 8 givenname: Ronen surname: Schneider fullname: Schneider, Ronen organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 9 givenname: Agape M surname: Awad fullname: Awad, Agape M organization: Department of Chemistry and Biochemistry and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California – sequence: 10 givenname: Anish surname: Nag fullname: Nag, Anish organization: Department of Chemistry and Biochemistry and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California – sequence: 11 givenname: Jang surname: Cho fullname: Cho, Jang organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 12 givenname: Markus surname: Schueler fullname: Schueler, Markus organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 13 givenname: Catherine F surname: Clarke fullname: Clarke, Catherine F organization: Department of Chemistry and Biochemistry and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California – sequence: 14 givenname: Rannar surname: Airik fullname: Airik, Rannar email: Friedhelm.Hildebrandt@childrens.harvard.edu, airikr@pitt.edu organization: Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania; and Friedhelm.Hildebrandt@childrens.harvard.edu airikr@pitt.edu – sequence: 15 givenname: Friedhelm surname: Hildebrandt fullname: Hildebrandt, Friedhelm email: Friedhelm.Hildebrandt@childrens.harvard.edu, airikr@pitt.edu organization: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Friedhelm.Hildebrandt@childrens.harvard.edu airikr@pitt.edu |
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| Keywords | focal segmental glomerulosclerosis nephrotic syndrome podocyte |
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| Title | Treatment with 2,4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific Coq6 Knockout Mice |
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