Search

Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first‐morning urine samples from individuals who were hypertensive who exhibited difficult‐to‐control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome‐wide associations with BP. We also analyzed nephron‐specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult‐to‐control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first‐morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP‐difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy‐to‐control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2‐fold change in the BP‐difficult group. In BP‐difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P=0.006) and Serpin Family B Member 9 (fold change, 5.10; P=0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP‐difficult group (P

Abstract Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI‐101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC‐secreted factor activity that was associated with anti‐inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI‐101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.