RGD Reference Report - Stim1 Polymorphism Disrupts Immune Signaling and Creates Renal Injury in Hypertension. - Rat Genome Database

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Stim1 Polymorphism Disrupts Immune Signaling and Creates Renal Injury in Hypertension.

Authors: Dhande, Isha S  Zhu, Yaming  Kneedler, Sterling C  Joshi, Aniket S  Hicks, M John  Wenderfer, Scott E  Braun, Michael C  Doris, Peter A 
Citation: Dhande IS, etal., J Am Heart Assoc. 2020 Mar 3;9(5):e014142. doi: 10.1161/JAHA.119.014142. Epub 2020 Feb 20.
RGD ID: 150429819
Pubmed: PMID:32075490   (View Abstract at PubMed)
PMCID: PMC7335582   (View Article at PubMed Central)
DOI: DOI:10.1161/JAHA.119.014142   (Journal Full-text)

Background Spontaneously hypertensive rats of the stroke-prone line (SHR-A3) develop hypertensive renal disease as a result of naturally occurring genetic variation. Our prior work identified a single-nucleotide polymorphism unique to SHR-A3 that results in truncation of the carboxy terminus of STIM1. The SHR-B2 line, which is also hypertensive but resists hypertensive renal injury, expresses the wild-type STIM1. STIM1 plays a central role in lymphocyte calcium signaling that directs immune effector responses. Here we show that major defects in lymphocyte function affecting calcium signaling, nuclear factor of activated T cells activation, cytokine production, proliferation, apoptosis, and regulatory T-cell development are present in SHR-A3 and attributable to STIM1. Methods and Results To assess the role of Stim1 variation in susceptibility to hypertensive renal injury, we created a Stim1 congenic line, SHR-A3(Stim1-B2), and STIM1 function was rescued in SHR-A3. We found that Stim1 gene rescue restores disturbed lymphocyte function in SHR-A3. Hypertensive renal injury was compared in SHR-A3 and the SHR-A3(Stim1-B2) congenic line. Histologically assessed renal injury was markedly reduced in SHR-A3(Stim1-B2), as were renal injury biomarker levels measured in urine. Stim1 deficiency has been linked to the emergence of antibody-mediated autoimmunity. Renal glomerular immunoglobulin deposition was greater in SHR-A3 than SHR-B2 and was reduced by Stim1 congenic substitution. Serum anti-double-stranded DNA antibody titers in SHR-A3 were elevated compared with SHR-B2 and were reduced in SHR-A3(Stim1-B2). Conclusions Stim1 deficiency in lymphocyte function originating from Stim1 truncation in SHR-A3 combines with hypertension to create end organ disease and may do so as a result of antibody formation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Hypertensive Nephropathy  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-(rs197197017-rs198445122)/Utx RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal calcium level  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx CD4+ T cellsRGD 
abnormal renal glomerulus morphology  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
albuminuria  IAGP 150429819compared to SHR/UtxRGD 
albuminuria  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
decreased IgG level  IAGP 150429819compared to SHR/Utx and SHRSP/BbbUtx renal anti-dsDNA antibodies at 18 weeks old RGD 
decreased interferon-gamma secretion  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx T cellsRGD 
decreased interleukin-2 secretion  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx T cellsRGD 
decreased regulatory T cell number  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx kidneyRGD 
decreased T cell apoptosis  IAGP 150429819compared to SHR/UtxRGD 
decreased T cell proliferation  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
increased B cell number  IAGP 150429819compared to SHR/Utx kidneyRGD 
increased B cell number  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx kidneyRGD 
increased CD4-positive, alpha-beta T cell number  IAGP 150429819compared to SHR/Utx kidneyRGD 
increased CD4-positive, alpha-beta T cell number  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx kidneyRGD 
increased CD8-positive, alpha-beta T cell number  IAGP 150429819compared to SHR/Utx kidneyRGD 
increased CD8-positive, alpha-beta T cell number  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx kidneyRGD 
increased IgM level  IAGP 150429819; 150429819compared to SHR/Utx renal anti-dsDNA antibodiesRGD 
increased T cell apoptosis  IAGP 150429819compared to SHR/Utx CD4+ T cellsRGD 
increased T cell number  IAGP 150429819compared to SHR/Utx kidneyRGD 
increased T cell number  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/Utx kidneyRGD 
increased urine HAVCR1 level  IAGP 150429819compared to SHR/UtxRGD 
increased urine HAVCR1 level  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
increased urine lipocalin 2 level  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
increased urine osteopontin level  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
tubulointerstitial nephritis  IAGP 150429819compared to SHR/Utx and SHRSP.SHR-rs197197017-rs198445122/UtxRGD 
Objects Annotated

Objects referenced in this article
Marker rs198445122 rs198445122 Rattus norvegicus
Marker rs197197017 rs197197017 Rattus norvegicus

Additional Information