Perivascular cells and their sub-types in healthy, aged and diseased kidney
Shaw, Isaac William
Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and these cause significant morbidity and mortality in hospital patients, either alone via renal failure or by aggravating other conditions such as cardiovascular disease. Perivascular cells of the vasculature, such as pericytes, have a major role in the progression of AKI and CKD. Their normal function in the kidney is to structurally support blood vessels, regulate blood pressure, and fine tune the distribution of blood flow, however they are activated following injury to perform new functions such as becoming myofibroblasts. The niches they occupy are diverse in both function and physiological environment, and there is heterogeneity in cell morphology and surface marker expression. However, little is known about the functional significance of this heterogeneity in the context of normal and diseased kidney. To investigate perivascular cell heterogeneity at homeostasis, common perivascular cell surface markers (CD146, PDGFR-β, PDGFR-α, NG2 and α-SMA) were used to identify and define subpopulations in mouse kidneys. The anatomical locations and relative numbers of these subpopulations were quantified in different kidney regions, and across a range of ages. It was found that perivascular cells are indeed highly heterogeneous with respect to these markers; markers are expressed to different degrees between regions, and broad patterns of marker expression are conserved in other species (cat, dog, human). To investigate perivascular cell response during injury, young (2 months) and old (18-24 months) mice were subjected to a moderate unilateral ischaemia-reperfusion injury (IRI), which preserves contralateral kidney function, and kidneys harvested at one, four and 28 days post-IRI. A dynamic response of the subpopulations was observed following injury, with both transient and sustained rises in the prevalence of certain markers and marker combinations, and this response was modified in aged animals. Injury was equivalent in young and old mice in this model. Subpopulations were sorted from murine kidneys via flow cytometry, however long term culture was not possible. Instead, because perivascular cells have been shown to give rise to mesenchymal stromal cells (MSCs), cultures were established of murine kidney-derived MSCs from different kidney regions. Using in vitro assays the effects of variation in renal physiological conditions, such as hypoxia and salt balance, on cell properties such as migration, viability and immunosuppression, were investigated in murine kidney- and human adipose-derived MSCs. Together this work highlights that the renal perivascular interstitial compartment comprises of a multitude of cell subpopulations that respond in idiosyncratic ways to kidney injury, and should therefore not be treated as one homogenous population. In addition, insights are made into how ageing, the strongest risk factor for CKD, affects the distribution of perivascular cell subpopulations and modifies their response to injury.