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Increased susceptibility to hypertensive renal disease in spontaneously hypertensive rats due to a mutation in Stim1

Emerging evidence implicates CD4+ T cells in the pathogenesis of hypertensive renal injury, though the underlying mechanisms that drive T cell dysfunction are not well understood. We identified a novel truncating mutation in the renal injury‐prone spontaneously hypertensive rat (SHR‐A3/SHRSP) line affecting the C‐terminus of STIM1, a protein involved in the store‐operated Ca2+ entry (SOCE) pathway. SOCE is required by T cells to activate the transcription factor NFAT and regulate T cell proliferation and cytokine production and regulatory T cell (Treg) development. In humans with loss‐of‐function mutations in Stim1, defective SOCE leads to a complex phenotype of immunodeficiency coupled with autoimmunity and uncontrolled lymphoproliferation. Our prior work identified defects in CD4+ T cell effector as well as regulatory function in SHR‐A3 rats as a result of impaired SOCE. We hypothesized that aberrant Stim1‐mediated SOCE leads to susceptibility to progressive renal injury in hypertension, potentially as a result of defective regulation of the immune response by T cells. Here, we test whether the emergence or renal injury in SHR‐A3 is affected by gene rescue of Stim1. A Stim1 congenic line (SHR‐A3(Stim1‐SHR‐B2)), in which the functional ‘wild type’ Stim1 allele was transferred from the SHR‐B2 line, which resists renal injury, into the injury‐susceptible SHR‐A3 genome. SOCE was restored to SHR‐B2 levels in the congenic SHR‐A3(Stim1‐SHR‐B2) line. This resulted in adequate NFAT activation (% cells with nuclear NFAT: 67±4.8 vs 8±3.8, p<0.001) in SHR‐A3(Stim1‐SHR‐B2) rats compared to SHR‐A3 rats. TCR‐induced lymphokine production was markedly higher in CD4+ T cells from SHR‐A3(Stim1‐SHR‐B2) compared with SHR‐A3 rats (IL‐2: 2074±367.1 vs 168±83.4 pg/mL, p<0.001; IFNγ: 2069±307.7 vs 235±69.5 pg/mL, p=0.002). Flow cytometric analysis of circulating T cell subsets revealed normalized CD4+CD25+FoxP3+ Treg frequencies in SHR‐A3(Stim1‐SHR‐B2) compared to SHR‐A3 (8.44±0.59 vs 4.34±0.59%, p=0.01). Restoration in SOCE in the congenic line was also associated with reduced renal T cell infiltration and decreased susceptibility to renal injury (uACR: 7.3±1.5 vs 13.4±2.9 p<0.05) at 40 weeks of age. Urinary renal injury biomarker levels were also lower in the congenic line than in SHR‐A3 rats at 30 weeks of age (KIM1: 0.7±0.07 vs 2.9±0.29 ng/mL, p<0.001; OPN: 6.9±1.4 vs 32.3±8.1 ng/mL, p<0.01; NGAL: 201.9±42.7 vs 1701±264.4 pg/mL, p<0.01). This correlated with lower renal injury scores assessed histologically. BP at 18 weeks, prior to the emergence of renal injury, was comparable between the SHR‐A3(Stim1‐SHR‐B2) and SHR‐A3 lines. Based on our findings, we conclude that defects in SOCE in SHR‐A3 attributable to the Stim1 mutation alter T cell function, reduce Treg numbers and may disturb regulatory interactions between T cells and other immune cells involved in hypertensive renal injury.