Jacqueline Ho

Fetal Alcohol Spectrum Disorder, caused by prenatal alcohol exposure, remains a major public health concern, affecting up to 1 in 20 U.S. schoolchildren. Pregnancy is typically not recognized until six weeks of gestation, alcohol exposure often occurs unknowingly during the peri-conceptional period, a highly vulnerable developmental window of oocyte maturation. The placenta is increasingly recognized as a mediator of alcohol-induced neurodevelopmental risk through the placenta–brain axis. We characterize peri-conceptional alcohol exposure on placental development in a mouse PCA model mimicking human drinking patterns. Single-cell transcriptomic analyses on late gestation placentas revealed disruption of extracellular matrix and collagen-remodeling pathways within the labyrinth; processes essential for placental vascular development. Mitochondria isolated from E17.5 placentas showed compromised respiration. We assess placental vascular functions with non-invasive dynamic contrast-enhanced MRI, enabling analysis across placental compartments for longitudinal evaluation of perfusion, substrate delivery, and contractile function. We demonstrate that PCA exposure arrests placental vascularization, perfusion, and morphological maturation. PCA exposure before implantation altered long-term placental programming, resulting in impaired placental perfusion and mitochondrial functions across gestation. These findings implicate placental dysfunction as a critical mechanism in Fetal Alcohol Spectrum Disorder pathogenesis and identify extracellular matrix remodeling and mitochondria as potential therapeutic targets following PCA exposure.

Background: Aldosterone promotes endothelial dysfunction and cardiovascular injury through mineralocorticoid receptor (MR) activation. Autophagy is essential for endothelial homeostasis, yet its role in aldosterone-mediated vascular dysfunction remains unclear. We tested whether aldosterone impairs autophagic flux and whether restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function. Methods: Endothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1-activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology. Results: Aldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner, indicated by LC3 accumulation and reduced p62 and BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone. Conclusions: Aldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.

Surgical transient occlusion of the renal pedicle induces renal ischemia–reperfusion injury (IRI), a widely used model for studying acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) in mice. However, conventional protocols often either preclude serum-based functional assessment or yield high mortality. While existing unilateral and bilateral renal IRI models emphasize reproducibility, challenges remain in achieving both consistent injury severity and long-term survival suitable for studying CKD progression. Here, we present a dorsal approach protocol that provides a robust and reproducible model of the ischemic AKI-to-CKD transition. The dorsal approach facilitates straightforward access to the kidneys and minimizes intra-abdominal manipulation. We use unilateral renal IRI combined with contralateral nephrectomy performed one day prior to blood and tissue collection. This approach offers two main advantages: (1) it minimizes variability by avoiding the inconsistencies associated with bilateral injury, and (2) it achieves nearly 100% survival while maintaining consistent injury, in contrast to protocols in which nephrectomy is performed earlier and associated with higher mortality. Functional evaluation is performed by serum BUN and creatinine, and interstitial fibrosis is quantified by Masson's trichrome-based collagen deposition and CKD marker genes at 28 and 42 days after renal IRI. Together, these readouts provide complementary insight into functional impairment and the development of tissue pathology. This protocol establishes a reliable and versatile model of ischemic-CKD in mice for mechanistic investigations.

Surgical transient occlusion of the renal pedicle induces renal ischemia–reperfusion injury (IRI), a widely used model for studying acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) in mice. However, conventional protocols often either preclude serum-based functional assessment or yield high mortality. While existing unilateral and bilateral renal IRI models emphasize reproducibility, challenges remain in achieving both consistent injury severity and long-term survival suitable for studying CKD progression. Here, we present a dorsal approach protocol that provides a robust and reproducible model of the ischemic AKI-to-CKD transition. The dorsal approach facilitates straightforward access to the kidneys and minimizes intra-abdominal manipulation. We use unilateral renal IRI combined with contralateral nephrectomy performed one day prior to blood and tissue collection. This approach offers two main advantages: (1) it minimizes variability by avoiding the inconsistencies associated with bilateral injury, and (2) it achieves nearly 100% survival while maintaining consistent injury, in contrast to protocols in which nephrectomy is performed earlier and associated with higher mortality. Functional evaluation is performed by serum BUN and creatinine, and interstitial fibrosis is quantified by Masson's trichrome-based collagen deposition and CKD marker genes at 28 and 42 days after renal IRI. Together, these readouts provide complementary insight into functional impairment and the development of tissue pathology. This protocol establishes a reliable and versatile model of ischemic-CKD in mice for mechanistic investigations.

Using a unique mouse model of prenatal exposure to maternal type 1 diabetes, our study demonstrates the novel observation that prenatal exposure to maternal diabetes results in a predisposition to high-salt (HS) dietary-induced vascular dysfunction and inflammation in adulthood. Mechanistically, we demonstrated that in utero exposure to maternal diabetes and HS intake induces vascular oxidative stress, cyclooxygenase-derived prostaglandin E₂, and inflammation.

Expression of the microRNA-17-92 cluster is upregulated by aldosterone in mouse cortical collecting duct principal cells, exclusively in female mice. MiR-19 in this cluster targets the serum and glucocorticoid kinase (SGK1) to downregulate both mRNA and protein expression, resulting in a decrease in sodium transport across epithelial cells of the collecting duct. The miR-17-92 cluster is evolutionarily conserved and may act as a novel feedback regulator for aldosterone signaling in females.

Background: Aldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of C-C Motif Chemokine Ligand 5 (CCL5) and its receptor, C-C Motif Chemokine Receptor 5 (CCR5), are well known in infectious diseases, but their roles in the genesis of aldosterone-induced vascular injury and hypertension are unknown. Methods: We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5 ^+/+ ) and CCR5 knockout (CCR5 ^−/− ) mice treated with aldosterone (600 µg/kg/day for 14 days) while receiving 1% saline to drink. Results: Here, we show that CCR5 plays a central role in aldosterone-induced vascular injury, hypertension, and renal damage. Long-term infusion of aldosterone in CCR5 ^+/+ mice resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression. Aldosterone treatment also triggered vascular injury, characterized by endothelial dysfunction and inflammation, hypertension, and renal damage. Mice lacking CCR5 were protected from aldosterone-induced vascular damage, hypertension, and renal injury. Mechanistically, we demonstrated that CCL5 increased NADPH oxidase 1 (Nox1) expression, reactive oxygen species (ROS) formation, NFκB activation, and inflammation and reduced nitric oxide production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aortae incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking Nox1, NFκB, or with Maraviroc treatment. Conclusions: Our data demonstrate that CCL5/CCR5, through activation of NFkB and Nox1, is critically involved in aldosterone-induced vascular and renal damage and hypertension. Our data place CCL5 and CCR5 as potential targets for therapeutic interventions in conditions with aldosterone excess.

MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.