APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease

Leslie A. Bruggeman, Zhenzhen Wu, Liping Luo, Sethu M. Madhavan, Martha Konieczkowski, Paul E. Drawz, David Thomas, Laura Barisoni-Thomas, John R. Sedor, John F. O'Toole

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

APOL1 risk variants are associatedwith kidney disease in blacks, but themechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes fromTg-G0 and Tg-G2mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.

Original languageEnglish (US)
Pages (from-to)3600-3610
Number of pages11
JournalJournal of the American Society of Nephrology
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Kidney Diseases
Pre-Eclampsia
Transgenic Mice
Podocytes
Placenta
Azotemia
Kidney
Litter Size
Eclampsia
Fetal Death
Autophagy
Weaning
Transgenes
Proteinuria
Primates
Necrosis
Genotype
Apoptosis
Pathology
Phenotype

ASJC Scopus subject areas

  • Nephrology

Cite this

Bruggeman, L. A., Wu, Z., Luo, L., Madhavan, S. M., Konieczkowski, M., Drawz, P. E., ... O'Toole, J. F. (2016). APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease. Journal of the American Society of Nephrology, 27(12), 3600-3610. https://doi.org/10.1681/ASN.2015111220

APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease. / Bruggeman, Leslie A.; Wu, Zhenzhen; Luo, Liping; Madhavan, Sethu M.; Konieczkowski, Martha; Drawz, Paul E.; Thomas, David; Barisoni-Thomas, Laura; Sedor, John R.; O'Toole, John F.

In: Journal of the American Society of Nephrology, Vol. 27, No. 12, 01.12.2016, p. 3600-3610.

Research output: Contribution to journalArticle

Bruggeman, LA, Wu, Z, Luo, L, Madhavan, SM, Konieczkowski, M, Drawz, PE, Thomas, D, Barisoni-Thomas, L, Sedor, JR & O'Toole, JF 2016, 'APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease', Journal of the American Society of Nephrology, vol. 27, no. 12, pp. 3600-3610. https://doi.org/10.1681/ASN.2015111220
Bruggeman, Leslie A. ; Wu, Zhenzhen ; Luo, Liping ; Madhavan, Sethu M. ; Konieczkowski, Martha ; Drawz, Paul E. ; Thomas, David ; Barisoni-Thomas, Laura ; Sedor, John R. ; O'Toole, John F. / APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 12. pp. 3600-3610.
@article{cf5c5782e8394333b023069d165e6034,
title = "APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease",
abstract = "APOL1 risk variants are associatedwith kidney disease in blacks, but themechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes fromTg-G0 and Tg-G2mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.",
author = "Bruggeman, {Leslie A.} and Zhenzhen Wu and Liping Luo and Madhavan, {Sethu M.} and Martha Konieczkowski and Drawz, {Paul E.} and David Thomas and Laura Barisoni-Thomas and Sedor, {John R.} and O'Toole, {John F.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1681/ASN.2015111220",
language = "English (US)",
volume = "27",
pages = "3600--3610",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "12",

}

TY - JOUR

T1 - APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease

AU - Bruggeman, Leslie A.

AU - Wu, Zhenzhen

AU - Luo, Liping

AU - Madhavan, Sethu M.

AU - Konieczkowski, Martha

AU - Drawz, Paul E.

AU - Thomas, David

AU - Barisoni-Thomas, Laura

AU - Sedor, John R.

AU - O'Toole, John F.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - APOL1 risk variants are associatedwith kidney disease in blacks, but themechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes fromTg-G0 and Tg-G2mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.

AB - APOL1 risk variants are associatedwith kidney disease in blacks, but themechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes fromTg-G0 and Tg-G2mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.

UR - http://www.scopus.com/inward/record.url?scp=85017205189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017205189&partnerID=8YFLogxK

U2 - 10.1681/ASN.2015111220

DO - 10.1681/ASN.2015111220

M3 - Article

VL - 27

SP - 3600

EP - 3610

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 12

ER -