Kidney degeneration goes hand in hand with cardiovascular disease and neurodegeneration in aging; kidney function is one of the better examples of the way in which deterioration in one organ system causes issues in many others. Nothing in our biology exists in isolation. Researchers here discuss the present state of knowledge regarding vascular calcification in the context of age-related chronic kidney disease. There is a particular focus on the role of chronic inflammation, given the way in which it disrupts all sorts of essential tissue maintenance processes. The accumulation of senescent cells is one of the more important contributions to chronic inflammation, and there is evidence for these cells to be influential in the calcification of blood vessels, and corresponding loss of flexibility.
Low kidney function is linked to poor health outcomes, with clinical manifestations in a wide variety of other organ systems, and is associated to a much higher risk of cardiovascular disease. The risk of cardiovascular disease exponentially increases as kidney function declines, being the major contributor to the high incidence of cardiovascular complications and death in this population. This is partially due to vascular calcification (VC) and accelerated atherosclerosis, as a result of the mineral and bone disorder that often accompanies low kidney function and complicates chronic kidney disease (CKD).
In addition to the complexity of mechanisms involved in VC initiation and progression, it is currently accepted that it cannot be regarded as an isolated pathological process, with several studies providing compelling evidence that VC is highly interconnected with inflammation. In fact, it has been suggested that pathological calcification and chronic inflammation are involved in a positive feedback loop driving disease progression.
Early stages of CKD are already associated with up-regulation of proinflammatory and pro-osteogenic molecules in the vascular wall and calcification of the aortic media. In fact, several lines of evidence indicate that inflammation triggers and precedes osteogenic conversion of vascular smooth muscle cells (VSMCs) and the release of calcifying extracellular vesicles (EVs), promoting the calcification process. It is likely that the effect of inflammation on VC occurs at multiple and interconnected levels. It has been proposed that inflammation might regulate VC, at least in part, through activation of an endoplasmic reticulum stress pathway, which in turn may increase inorganic phosphate uptake, leading to increased VSMCs osteogenic differentiation and increased mineral deposition.
Remarkably, this inflammation/vascular calcification crosstalk described in CKD pathology shares many similarities with the aging process in the general population, including the inflammaging and VSMCs senescence. Inflammaging is a recently adopted term do define a state of low grade chronic inflammatory condition, associated with a significant risk factor for morbidity and mortality in the elderly. Cellular senescence, in general, has been proposed as a potential mechanism of aging and age-related diseases, which can be triggered by a number of mechanisms and leading to an altered secretome, termed the senescence-associated secretory phenotype (SASP). In the particular case of VSMCs, senescence has been shown to enhance vascular calcification and inflammation, with pro-calcific and pro-inflammatory SASPs.
VSMCs senescence and associated SASP have been suggested to contribute to chronic vascular inﬂammation and calcification, loss of arterial function, and the development of age-related diseases. Thus, it has been suggested that altered vascular health under CKD settings might represent an example of premature aging. In this context, it could be conceivable that new knowledge about molecular mechanisms, such as the crosstalk between VC and inflammation, in CKD, might shed new light on the aging process, and vice versa.