Mesenchymal stem cell-like (MSC-like) cells reside in the vascular wall but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells, and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during athero- and arteriosclerosis in ApoE−/− mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.

Klotho protects the kidney from ischemia-reperfusion injury, but its effect on nephrotoxins is unknown. Here we determined if Klotho protects the kidney from cisplatin toxicity. Cisplatin increased plasma creatinine and induced tubular injury, which were exaggerated in Klotho haplosufficient (Kl/+) and ameliorated in transgenic Klotho overexpressing (Tg-Kl) mice. Neutrophil gelatinase-associated lipocalin and active caspase-3 protein, and number of apoptotic cells in the kidney were higher in Kl/+ and lower in Tg-Kl compared to wild type mice. Klotho suppressed basolateral uptake of cisplatin by the normal rat kidney cell line (NRK); an effect similar to cimetidine, a known inhibitor of organic cation transport (OCT). A decrease in cell surface and total OCT2 protein and OCT activity by Klotho was mimicked by glucuronidase. The Klotho effect was attenuated by glucuronidase inhibition. On the other hand, OCT2 mRNA was reduced by Klotho, but not β-glucuronidase. Moreover, cimetidine inhibited OCT activity but not OCT2 expression. Unlike cimetidine, Klotho reduced cisplatin-induced apoptosis from either the basolateral or apical side, and even when added after NRK cells were already loaded with cisplatin. Thus, Klotho protects the kidney against cisplatin nephrotoxicity by reduction of basolateral uptake of cisplatin by OCT2, and a direct anti-apoptotic effect independent of cisplatin uptake. Klotho may be a useful agent to prevent and treat cisplatin-induced nephrotoxicity.

Terminally differentiated cells can be reprogrammed to pluripotency or directly to another differentiated cell type in vitro, a capacity termed cellular plasticity. Plasticity is not limited to in vitro manipulations but rather represents an important aspect of the regenerative response to injury in organs. Differentiated adult cells retain the capacity to dedifferentiate, adopting a progenitor-like phenotype after injury or, alternatively, to transdifferentiate, directly converting to a different mature cell type. Emerging concepts on cellular plasticity have relevance to our understanding of repair after kidney injury, including epithelial regeneration. Here we discuss work published in the past 5 years on the cellular hierarchies and mechanisms underlying kidney injury and repair, with a particular focus on potential roles for cellular plasticity in this response.

Conflict of interest: BDH is a scientific cofounder of and holds equity in Chinook Therapeutics, a biotechnology company seeking to develop drugs to treat kidney diseases.

Peritubular capillary rarefaction is hypothesized to contribute to the increased risk of future CKD after AKI. Here, we directly tested the role of Gli1 kidney pericytes in the maintenance of peritubular capillary health, and the consequences of pericyte loss during injury. Using bigenic Gli1-CreER; R26tdTomato reporter mice, we observed increased distance between Gli1 pericytes and endothelial cells after AKI (mean±SEM: 3.3±0.1 m before injury versus 12.5±0.2m after injury; <0.001). Using a genetic ablation model, we asked whether pericyte loss alone is sufficient for capillary destabilization. Ten days after pericyte ablation, we observed endothelial cell damage by electron microscopy. Furthermore, pericyte loss led to significantly reduced capillary number at later time points (mean±SEM capillaries/high-power field: 67.6±4.7 in control versus 44.1±4.8 at 56 days; <0.05) and increased cross-sectional area (mean±SEM: 21.9±0.4 m in control versus 24.1±0.6 m at 10 days; <0.01 and 24.6±0.6 m at 56 days; <0.001). Pericyte ablation also led to hypoxic focal and subclinical tubular injury, reflected by transient expression of Kim1 and vimentin in scattered proximal tubule segments. This analysis provides direct evidence that AKI causes pericyte detachment from capillaries, and that pericyte loss is sufficient to trigger transient tubular injury and permanent peritubular capillary rarefaction.