Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models

Santosh L. Saraf, Justin R. Sysol, Alexandru Susma, Suman Setty, Xu Zhang, Krishnamurthy P. Gudehithlu, Jose A.L. Arruda, Ashok K. Singh, Roberto Machado, Victor R. Gordeuk

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso-occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. Using transgenic sickle mice, we investigated the histopathologic, ultrastructural, and gene expression differences with the HbS mutation. Consistent with progressive glomerular damage, we observed progressively greater urine protein concentrations (P = 0.03), glomerular hypertrophy (P = 0.002), and glomerular cellularity (P = 0.01) in HbAA, HbAS, and HbSS mice, respectively. Ultrastructural studies demonstrated progressive podocyte foot process effacement, glomerular basement membrane thickening with reduplication, and tubular villous atrophy with the HbS mutation. Gene expression studies highlighted the differential expression of several genes involved in prostaglandin metabolism (AKR1C18), heme and iron metabolism (HbA-A2, HMOX1, SCL25A37), electrolyte balance (SLC4A1, AQP6), immunity (RSAD2, C3, UBE2O), fatty acid metabolism (FASN), hypoxia hall-mark genes (GCK, SDC3, VEGFA, ETS1, CP, BCL2), as well as genes implicated in other forms of kidney disease (PODXL, ELMO1, FRMD3, MYH9, APOA1). Pathway analysis highlighted increased gene enrichment in focal adhesion, extracellular matrix-receptor interaction, and axon guidance pathways. In summary, using transgenic sickle mice, we observed that inheritance of the HbS mutation is associated with glomerular and tubular damage and identified several candidate genes and pathways for future investigation in sickle cell trait and sickle cell anemia-related kidney disease.

Original languageEnglish (US)
JournalTranslational Research
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Sickle Cell Trait
Kidney Diseases
Sickle Cell Anemia
Genes
Mutation
Metabolism
Gene Expression
African Americans
Transgenic Mice
Gene expression
Sickle Hemoglobin
Podocytes
Glomerular Basement Membrane
Focal Adhesions
Water-Electrolyte Balance
Hemolysis
Heme
varespladib methyl
Polymerization
Hypertrophy

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical

Cite this

Saraf, S. L., Sysol, J. R., Susma, A., Setty, S., Zhang, X., Gudehithlu, K. P., ... Gordeuk, V. R. (Accepted/In press). Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models. Translational Research. https://doi.org/10.1016/j.trsl.2018.01.007

Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models. / Saraf, Santosh L.; Sysol, Justin R.; Susma, Alexandru; Setty, Suman; Zhang, Xu; Gudehithlu, Krishnamurthy P.; Arruda, Jose A.L.; Singh, Ashok K.; Machado, Roberto; Gordeuk, Victor R.

In: Translational Research, 01.01.2018.

Research output: Contribution to journalArticle

Saraf, SL, Sysol, JR, Susma, A, Setty, S, Zhang, X, Gudehithlu, KP, Arruda, JAL, Singh, AK, Machado, R & Gordeuk, VR 2018, 'Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models', Translational Research. https://doi.org/10.1016/j.trsl.2018.01.007
Saraf, Santosh L. ; Sysol, Justin R. ; Susma, Alexandru ; Setty, Suman ; Zhang, Xu ; Gudehithlu, Krishnamurthy P. ; Arruda, Jose A.L. ; Singh, Ashok K. ; Machado, Roberto ; Gordeuk, Victor R. / Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models. In: Translational Research. 2018.
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abstract = "Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso-occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. Using transgenic sickle mice, we investigated the histopathologic, ultrastructural, and gene expression differences with the HbS mutation. Consistent with progressive glomerular damage, we observed progressively greater urine protein concentrations (P = 0.03), glomerular hypertrophy (P = 0.002), and glomerular cellularity (P = 0.01) in HbAA, HbAS, and HbSS mice, respectively. Ultrastructural studies demonstrated progressive podocyte foot process effacement, glomerular basement membrane thickening with reduplication, and tubular villous atrophy with the HbS mutation. Gene expression studies highlighted the differential expression of several genes involved in prostaglandin metabolism (AKR1C18), heme and iron metabolism (HbA-A2, HMOX1, SCL25A37), electrolyte balance (SLC4A1, AQP6), immunity (RSAD2, C3, UBE2O), fatty acid metabolism (FASN), hypoxia hall-mark genes (GCK, SDC3, VEGFA, ETS1, CP, BCL2), as well as genes implicated in other forms of kidney disease (PODXL, ELMO1, FRMD3, MYH9, APOA1). Pathway analysis highlighted increased gene enrichment in focal adhesion, extracellular matrix-receptor interaction, and axon guidance pathways. In summary, using transgenic sickle mice, we observed that inheritance of the HbS mutation is associated with glomerular and tubular damage and identified several candidate genes and pathways for future investigation in sickle cell trait and sickle cell anemia-related kidney disease.",
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AU - Zhang, Xu

AU - Gudehithlu, Krishnamurthy P.

AU - Arruda, Jose A.L.

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