Project

renal failure; vascular calcification; sodium thiosulfate; uremia; vascular smooth muscel cell

Lead
Lay summary
Lead: Renal function is of pivotal relevance for the normal physiology of the body. As a corollary, diminished renal function has devastating consequences on other organs. The cardiovascular sequelae accounting for at least 50% of deaths in patients with chronic renal failure have emerged as a major public health problem. Besides the traditional cardiovascular risk factors, patients with chronic renal failure exhibit accelerated arterial calcifications leading to arterial stiffness and heart damage.Background: The mechanisms for vascular calcification are only partly understood. Factors discussed to be relevant for modulating the calcifying propensity of blood vessel walls comprise, among others, high calcium and phosphate concentrations, microinflammation and diminished activity of calcification-inhibitory proteins. Recently, evidence emerged that vascular smooth muscle cells (VSMC) exposed to a uremic milieu loose smooth muscle specific gene expression and upregulate bone cell specific genes, a process called "transdifferentiation". Therapeutic or preventive strategies for uremic vascular calcifications are scarce and mostly still experimental. We recently demonstrated for the first time that sodium thiosulfate (STS) prevents aortic calcifications in rats with impaired renal function, an effect associated with calcium-chelating and acidosis inducing properties of STS. The major side effect of STS encountered was decreased bone strength.Hypothesis: We hypothesize now that STS has specific effects on the uremia-induced transdifferentiation process of VSMCs to "osteoblast-like" cells in vitro and that inhibition of this process prevents and/or reverses vascular calcification in vivo. Methods: In the project mentioned here we will first treat uremic rats with different agents and STS in order to dissect whether the beneficial effect of STS is due to the lower pH, the calcium binding property, the sulphur load or another specific STS-mediated mechanism. The same agents will be incubated with rat vascular smooth muscle cells (VSMC) in a uremic milieu in order to dissect whether the VSMC transdifferentiation can be inhibited by changing pH, chelation, sulphur load or another mechanism.Second, we will decipher the transcriptional profile by Genechips of VSMC, isolated from the aorta of the rats and from the culture experiments mentioned above, in order to identify potential pathways involved in the calcification preventive effect of STS.Thiosulfate is a natural product, present as an endogenous metabolite in mammalians, including humans. Its biological effects are therefore of interest even beyond its preventive effect on calcification in uremia.

Direct link to Lay Summary

Last update: 21.02.2013

Title	Year

Renal function is of pivotal relevance for the normal physiology of the mammalian body. As a corollary, diminished renal function has devastating consequences on other organs. Recently, the cardiovascular sequelae accounting for at least 50% of deaths in patients with chronic renal failure have emerged as a major public health problem. Besides the traditional cardiovascular risk factors, patients with chronic renal failure exhibit accelerated arterial calcifications leading to arterial stiffness and left ventricular hypertrophy.The mechanisms for vascular calcification are only partly understood. Factors discussed to be relevant for modulating the calcifying propensity of blood vessel walls in uremia comprise, among others, high calcium and phosphate concentrations, microinflammation, fetuin-A, matrix Gla protein (MGP), carboanhydrase or osteoprotegerin. Recently, evidence emerged that vascular smooth muscle cells (VSMC) exposed to a uremic milieu loose smooth muscle specific gene expression and upregulate bone cell specific genes, a process called “transdifferentiation”. Therapeutic or preventive strategies for uremic vascular calcifications are scarce and by and large still experimental. We recently demonstrated for the first time that sodium thiosulfate (STS) prevents aortic calcifications in rats with impaired renal function, an effect associated with calcium-chelating and acidosis inducing properties of STS and increased MPG levels (1). The major side effect of STS encountered was decreased bone strength. We hypothesize now that STS has specific effects on the uremia-induced transdifferentiation process of VSMCs to “osteoblast like” cells in vitro and that inhibition of this process prevents and/or reverses vascular calcification in vivo. Specifically we propose:First, to treat uremic rats with NH3Cl(acidosis) or EDTA (Ca-chelation), or Na2SO4 (sulphur) or STS (controls) in order to dissect whether the beneficial effect of STS is due to the lower ph, the calcium binding property, the sulphur load or another specific STS-mediated mechanism. The same agents will be incubated with rat smooth muscle cells (SMC) in a uremic milieu in order to dissect whether the VSMC transdifferentiation can be inhibited by changing pH, chelation, sulphur load or another mechanism.Second, to decipher the transcriptional profile by Affymetrix Genechips of VSMC, isolated from the aorta of the rats and from the culture experiments mentioned above, in order to identify potential pathways involved in the calcification preventive effect of STS.Relevance: STS is a natural product, present as an endogenous metabolite in mammalians, including humans. Its biological effects are therefore of interest even beyond its preventive effect on calcification in uremia.