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.

Comprehensive Bioinformatics Analysis Identifies POLR2I as a Key Gene in the Pathogenesis of Hypertensive Nephropathy

“…These results indicated that HN is possibly a disorder caused by abnormalities in transcription activity and imbalance in redox homeostasis. As previously reported, the abnormal transcription activity of genes (Zhang et al, 2015;Dhande et al, 2020) and oxidative stress (Majzunova et al, 2019;Nguyen et al, 2020) can be a cause or, more often, a potentiating factor for hypertension and hypertensive renal disease. Besides this, three hub genes associated with HN, namely, POLR2L, POLR2G, and POLR2I, were identified by PPI network analysis.…”

Emerging Insights Into Chronic Renal Disease Pathogenesis in Hypertension From Human and Animal Genomic Studies

“… 114 Replacement of the defective Stim1 allele in SHR-A3 remedies defective Ca ++ signaling and substantially reduces renal injury without effect on preinjury BP. 114 Rare genetic defects in humans producing complete loss of Stim1 function are associated with autoimmune disease attributable to disturbed antibody formation. 115 , 116 Thus, SHR-A3 has accumulated 2 gene variants with important consequences for antibody formation that drive renal injury in the presence of hypertension.…”

Genetic susceptibility of hypertension‐induced kidney disease

“…They concluded that there are one or more genes in the IgH region of chromosome 6 likely influence renal injury by altering B‐ and T‐cell function and the immune response. In subsequent studies, they identified a truncation in another gene ( Stim1 ) in the SpSHR rats that contribute to the susceptibility to renal injury (Dhande et al., 2020). STIM1 is an endoplasmic reticulum (ER) calcium sensor that plays a central role in lymphocyte effector and regulatory function.…”

“…STIM1 is an endoplasmic reticulum (ER) calcium sensor that plays a central role in lymphocyte effector and regulatory function. Congenic replacement of truncated Stim1 with the wild‐type allele restored a major defect in immune function in SHR‐A3, a line of SpSHR, and the ability of hypertension to elicit damage to the kidney was reduced in this model (Dhande et al., 2020). These results suggest that the major immune phenotype produced by the Stim1 mutation participates in renal injury in SHR‐A3, and this may include injury contributed by autoantibody formation that interferes with T‐cell signaling to program antibodies producing by B cells.…”