Stim1 Polymorphism Disrupts Immune Signaling and Creates Renal Injury in Hypertension

Abstract

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 STIM 1. The SHR ‐B2 line, which is also hypertensive but resists hypertensive renal injury, expresses the wild‐type STIM 1. STIM 1 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.