Publications by authors named "Ingrid M van den Berg-Garrelds"

2 Publications

  • Page 1 of 1

Selective PDE1 inhibition ameliorates vascular function, reduces inflammatory response, and lowers blood pressure in ageing animals.

J Pharmacol Exp Ther 2021 Jun 7. Epub 2021 Jun 7.

Erasmus MC, Netherlands

Diminished nitric oxide - cGMP -mediated relaxation plays a crucial role in cardiovascular ageing, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately cardiovascular dysfunction. Ageing is the time-related worsening of physiological function due to complex cellular and molecular interactions, and is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice provides us an efficient tool to accelerate vascular ageing, explore mechanisms, and test potential treatments. Previously we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular ageing. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular ageing features in mice. Compared to wild-type mice, mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in mice. An 8-week treatment with 100 mg/kg/d ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in mice. These findings suggest PDE1 inhibition would provide a powerful tool for nitric oxide - cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to ageing. The findings implicate the key role of PDE1 in vascular function and might be of clinical importance for prevention of mortalities and morbidities related to vascular complications during ageing, as well as for progeria patients that show a high risk of cardiovascular disease.
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http://dx.doi.org/10.1124/jpet.121.000628DOI Listing
June 2021

Human kidney organoids produce functional renin.

Kidney Int 2021 01 9;99(1):134-147. Epub 2020 Sep 9.

Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Renin production by the kidney is of vital importance for salt, volume, and blood pressure homeostasis. The lack of human models hampers investigation into the regulation of renin and its relevance for kidney physiology. To develop such a model, we used human induced pluripotent stem cell-derived kidney organoids to study the role of renin and the renin-angiotensin system in the kidney. Extensive characterization of the kidney organoids revealed kidney-specific cell populations consisting of podocytes, proximal and distal tubular cells, stromal cells and endothelial cells. We examined the presence of various components of the renin-angiotensin system such as angiotensin II receptors, angiotensinogen, and angiotensin-converting enzymes 1 and 2. We identified by single-cell sequencing, immunohistochemistry, and functional assays that cyclic AMP stimulation induces a subset of pericytes to increase the synthesis and secretion of enzymatically active renin. Renin production by the organoids was responsive to regulation by parathyroid hormone. Subcutaneously implanted kidney organoids in immunodeficient IL2Ry/-Rag2 mice were successfully vascularized, maintained tubular and glomerular structures, and retained capacity to produce renin two months after implantation. Thus, our results demonstrate that kidney organoids express renin and provide insights into the endocrine potential of human kidney organoids, which is important for regenerative medicine in the context of the endocrine system.
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http://dx.doi.org/10.1016/j.kint.2020.08.008DOI Listing
January 2021