Lishu He

Hypertension is a leading cause of disease burden and mortality. Here, we present a single-cell analysis of hypertension and end-organ damage across six organs and tissues in angiotensin II–treated mice, Dahl salt–sensitive rats, and spontaneously hypertensive rats. We identified gene programs associated with blood pressure and renal injury, including a conserved vascular smooth muscle cell program and cross-segment renal tubular programs, along with tissue-specialized endothelial adaptations and coordinated changes across cell types in select organs. Integration with human genomic data revealed model-specific and shared cell type–trait links. We prioritized a noncoding variant (rs28451064) and used genome editing to demonstrate its in vivo effect on blood pressure and allele-specific regulation of local genes. Our study provides a multimodel, cross-organ cellular resource for hypertension research.

Background: While previous studies have largely overlooked the potential correlation between the waist-to-height ratio (WHtR) and microalbuminuria in Chinese adults, this study aims to rigorously investigate this relationship. Specifically, we examined the potential nonlinear association between WHtR and the presence of microalbuminuria. Methods: We conducted a cross-sectional analysis of 33,685 participants from eight regions across China. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (ACR) > 30 mg/g. The relationship between WHtR and microalbuminuria was assessed using univariate and multivariate logistic regression models. We further explored potential nonlinear associations using Generalized Additive Models (GAM) and evaluated threshold effects to identify critical inflection points. Subgroup analyses were performed to validate the robustness of our findings. Results: The cohort (N = 33,685) had a mean age of 57.6 ± 9.27 years and was predominantly females (22,516; 66.8%). The mean WHtR was 0.537 ± 0.06. The median ACR value observed was 9.93 mg/g with an interquartile range (IQR) of 8.23–11.68 mg/g. Notably, the prevalence rate of microalbuminuria detected in the study was 14.4%. In multivariate-adjusted models, each one-unit increase in WHtR was associated with a 48.3% higher likelihood of microalbuminuria development (odds ratio [OR] = 1.483; 95% confidence interval [CI]: 1.410–1.559; p < 0.0001). GAM analyses revealed a significant non-linear association between WHtR and microalbuminuria ( p < 0.0001). Segmented logistic regression identified a WHtR threshold value of 0.497. Above this threshold, the risk of microalbuminuria increased markedly (OR = 11.9, 95% CI 5.14–27.56, p < 0.0001), whereas below this threshold, WHtR was inversely associated with microalbuminuria (OR = 0.107, 95% CI: 0.015–0.748, p = 0.0243). Subgroup analyses further indicated a stronger association among individuals without hypertension and those with a body mass index (BMI) ≥ 24 kg/m ² , while the association was attenuated in hypertensive participants and those with a BMI < 24 kg/m ² . Conclusions: The risk of microalbuminuria exhibited a U-shaped pattern across WHtR values, with elevated risk at both low and high ends of the spectrum. Moderate central adiposity appeared to confer a protective effect against renal dysfunction. These findings highlighted the dual risks posed by underweight and excessive abdominal obesity and underscored the importance of targeted strategies to prevent obesity-related kidney damage. Future research is warranted to elucidate the mechanisms by which excess visceral fat contributes to renal impairment and to guide interventions aimed at preserving kidney health in diverse populations.

Several microRNAs (miRNAs) strongly influence blood pressure and the development of hypertension by modulating vascular, renal, and other physiological mechanisms. In addition, miRNAs may contribute to the genetic regulation of blood pressure. Future research should focus on investigating select miRNAs with potent physiological effects, understanding cellular context–dependent mechanisms conferring specificity to miRNA action, and integrating miRNAs as powerful modulators into the molecular system that underlies the regulation of blood pressure and the development of hypertension.

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDL receptor (LDLR) regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we have identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silico analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of the (P)RR mRNA. Mutating the binding sites for miR-148a in the 3’-UTR of (P)RR mRNA completely abolished the inhibitory effects of miR-148a on (P)RR expression. In line with our recent findings, reduced (P)RR expression resulted in decreased cellular LDL uptake, likely as a consequence of decreased LDLR protein abundance. Overexpressing the (P)RR prevented miR-148a-induced reduction in LDLR abundance and cellular LDL uptake. Our study supports a new concept that miR-148a is a regulator of (P)RR expression. By reducing (P)RR abundance, miR-148a decreases LDLR protein abundance and consequently cellular LDL uptake.

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDLR regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silicon analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of (P)RR mRNA. Mutating the binding sites for miR-148a in the 3’-UTR of (P)RR mRNA abolished the inhibitory effects of miR-148a on (P)RR expression. In line with our recent findings, reduced (P)RR expression resulted in decreased cellular LDL uptake, likely as a consequence of decreased LDLR protein abundance. Overexpressing the (P)RR prevented miR-148a-induced reduction in LDLR abundance and cellular LDL uptake. Our study supports a new concept that miR-148a is a regulator of (P)RR expression. By reducing (P)RR abundance, miR-148a decreases LDLR protein abundance and consequently cellular LDL uptake.