Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

Abstract

Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-like receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single-cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic.

Keywords: kidney injury; molecular mechanisms; molecular signature; renal progenitors; single-cell RNA sequencing.

Figure 1

Main molecular mechanisms controlling renal progenitor responses in physiological and pathological conditions: (A) glomerular progenitors and (B) tubular progenitors. β-cat: β-catenin, CXCL12: C-X-C Motif Chemokine Ligand 12, Dach1: Dachshund homolog 1, ROCK: Rho kinase, Ang II/AT1: Angiotensin II/Angiotensin II receptor, IFN-α/IFN-β: interferon-α and interferon-β, BMP-7: bone morphogenetic protein 7, Bmi-1: B lymphoma Mo-MLV insertion region 1 and TLR2: Toll-like receptor 2.

Figure 2

Adult kidney progenitor cells secrete soluble molecules, as well as molecule-containing extracellular vesicles, that contribute to the regeneration of the kidneys. miR: microRNA, HGF: hepatocyte growth factor, EGF: epidermal growth factor, TGF-β: transforming growth factor-β, Epo: erythropoietin, CXCL6: C-X-C motif chemokine ligand 6, SAA2: serum amyloid A2, SAA4: serum amyloid A4, BPIFA2: BPI (bactericidal permeability-increasing) fold-containing family A member 2, VEGF: vascular endothelial growth factor and BMP-7: bone morphogenetic protein 7.