Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

7 Warning Signs Of High Blood Pressure That Should Not Be Ignored

Hypertension, known as High Blood Pressure in layman language, occurs when the force of blood against the artery walls is consistently too high. On a global level, this has been set to any reading beyond 120/80 (the systolic pressure (top number, when the heart beats) and the diastolic pressure (bottom number, when the heart is at rest), though it can vary greatly due to age, gender, weight etc. Known as the "silent killer", hypertension is mostly genetic, though it can also occur in individuals with no family history. The condition can lead to heart disease and stroke, and can be fatal if not controlled. It can sometimes have no known symptoms, but here are 7 warning signs that your BP is high, and you need help...

High Soluble Klotho Levels Linked To Lower CKD Prevalence In Adults With Diabetes, Hypertension

New research reveals how serum soluble Klotho levels relate to chronic kidney disease risk (CKD) in patients with diabetes and hypertension.

The findings suggest hypertension as a modifier in the relationship between sKlotho and CKD prevalence.

Image credit: luchschenF - stock.Adobe.Com

New findings shed light on the relationship between serum soluble Klotho (sKlotho) and chronic kidney disease (CKD) in diabetes, the topic of a long-standing, controversial discussion.1 Among individuals with diabetes and hypertension, those with higher levels of sKlotho, a protein known to protect kidney function, showed a significantly lower prevalence of CKD.

Previous studies have linked Klotho and hypertension; however, current treatments primarily focus on reducing blood pressure instead of addressing the underlying causes, as the mechanisms behind hypertension are not fully understood.2

This study aimed to explore the highly debated role of sKlotho in diabetic kidney disease and as it relates to hypertension.1 "Our results confirmed a negative association between sKlotho levels and CKD prevalence in adults with [diabetes], which was observed only in participants with hypertension," the authors wrote.

The study analyzed data from 3302 adults aged 40 and older with diabetes who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016. Using multivariate logistic regression models stratified by hypertension status, they found that the prevalence of CKD was lower among individuals with both diabetes and hypertension who had high sKlotho levels (≥ 806 pg/mL), compared with those with low levels (< 806 pg/mL). The adjusted OR for CKD in this group was 0.54 (95% CI, 0.41-0.72; P < .001).

Critically, no such association between sKlotho and CKD was observed in those with diabetes but without hypertension. The researchers also found a statistically significant interaction between hypertension and sKlotho on both additive and multiplicative scales (0.65; 95% CI, 0.42-0.99), indicating a synergistic effect, where the combined presence of low sKlotho and hypertension posed a greater risk for CKD than either factor alone.

Among participants with diabetes and without hypertension, researchers observed a trend: individuals with very high sKlotho levels (> 1400 pg/mL) appeared to have a higher prevalence of CKD. Further analysis suggested that these individuals also had higher blood glucose and kidney function markers, potentially reflecting more intensive use of anti-diabetic medications, some of which are known to upregulate Klotho expression. However, the implications of this observation remain unclear and warrant further investigation.

The cross-sectional design limits the ability to draw causal inferences, and the researchers acknowledged that reverse causality and unmeasured confounding may be present. Furthermore, sKlotho levels and kidney function were measured at a single time point, which limits assessment of temporal relationships. The study population also only included US adults, which may restrict the generalizability of the findings to other regions or ethnic groups.

While the casualties of these associations demand further investigation, the authors concluded that the findings suggest hypertension as a modifier in the relationship between sKlotho and CKD prevalence, potentially explaining past inconsistencies in the literature.

References

1. Hong T, Lian Z, Zhang C, Zhang W, Ye Z. Hypertension modifies the association between serum Klotho and chronic kidney disease in US adults with diabetes: a cross-sectional study of the NHANES 2007-2016. Ren Fail. 2025;47(1):2498089. Doi:10.1080/0886022X.2025.2498089

2. Kanbay M, Demiray A, Afsar B, et al. Role of Klotho in the development of essential hypertension. Hypertension. 2021;77(3):740-750. Doi:10.1161/hypertensionaha.120.16635

A Renal Protein Reveals A New Mechanism In Hypertension

UNIGE scientists discovered a new mechanism involved in blood pressure regulation, opening the door to novel therapeutic approaches.

Localisation of paracingulin (green) and sodium and chloride ion cotransporter (red) by immunofluorescence on a mouse kidney section. Cell nuclei are shown in blue. © Sandra Citi

Hypertension affects nearly one in three adults worldwide and is one of the major risk factors for cardiovascular disease. Previous studies suggest that the junctional protein paracingulin plays a role in the development of hypertension, but the underlying mechanisms remain poorly understood. Scientists from the University of Geneva (UNIGE) developed a mouse model of hypertension to understand the mechanisms through which the loss of paracingulin attenuates the development of hypertension. The team now confirms its essential role in the development of hypertension and provides an in-depth analysis of this mechanism. The results have been published in the American Journal of Physiology, Renal Physiology.

Blood pressure refers to the force exerted by the blood as it flows through the blood vessels. It is regulated by several factors, including the kidneys. By filtering blood, the kidneys control the amount of salt and water excreted in urine, which directly affects blood volume and, consequently, blood pressure. In addition, hormones such as angiotensin II and aldosterone stimulate the body to retain sodium and constrict blood vessels. This regulatory system keeps blood pressure within an optimal range but can become dysregulated, leading to hypertension—a major cardiovascular health risk.

Our results suggest that the protection against hypertension is linked to kidney function, not blood vessel constriction.

The Dahl Rat Model for Studying Hypertension

A well-known animal model, the Dahl rat (named after the American researcher who developed it), has been used for decades to study hypertension. This rat strain spontaneously develops high blood pressure when fed a high-salt diet. However, it was previously reported that in the absence of a cell junction protein called paracingulin (CGNL1), these rats do not develop hypertension, even on a high-salt diet.

Sandra Citi, Associate Professor in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science, is a specialist in cell-cell junctions. These protein-based ''locks'' connect neighboring cells to maintain tissue integrity and control the passage of ions and nutrients across tissue compartments. In collaboration with Eric Feraille, Full Professor in the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine and a specialist in kidney physiology, Sandra Citi's team investigated the role of paracingulin in hypertension. After creating a knock-out of CGNL1 in mice, they observed that the loss of paracingulin protects against angiotensin II-induced hypertension.

A Kidney-Specific Effect

Angiotensin II-induced hypertension involves the activation of sodium transporters in the kidneys. The researchers thus analyzed the levels of activated transporters in the kidneys lacking paracingulin. "We did not observe activation of the transporters. Our results suggest that the protection against hypertension is linked to kidney function, not blood vessel constriction," explains Florian Rouaud, Senior Research Assistant in the Department of Molecular and Cellular Biology at UNIGE and first author of the study. "In the absence of CGNL1, angiotensin II can no longer activate certain sodium transporters in the renal tubules, which prevents the body from retaining salt and water, and therefore from increasing blood pressure."

A Novel Therapeutic Avenue

This study identifies paracingulin for the first time as a key player in the renal signaling of angiotensin II—a pathway where junctional proteins were not known to be implicated. It could eventually lead to the development of new therapeutic strategies targeting this protein, as a complement to current treatments, which are often based on inhibitors of the renin-angiotensin system.

Downloade the PDF version Contact

Sandra CitiAssociate ProfessorDepartment of Molecular and Cellular Biology Faculty of ScienceUNIGE+41 22 379 61 82Sandra.Citi(at)unige.Ch

Eric FerailleFull ProfessorDepartment of Cell Physiology and MetabolismUNIGE+41 22 379 52 82Eric.Feraille(at)unige.Ch

High resolution pictures

This research is published inAmerican Journal of Physiology, Renal PhysiologyDOI: 10.1152/ajprenal.00271.2024

---