Kidney-derived c-kit+ progenitor/stem cells contribute to podocyte recovery in a model of acute proteinuria.

Abstract

Kidney-derived c-kit+ cells exhibit progenitor/stem cell properties and can regenerate epithelial tubular cells following ischemia-reperfusion injury in rats. We therefore investigated whether c-kit+ progenitor/stem cells contribute to podocyte repair in a rat model of acute proteinuria induced by puromycin aminonucleoside (PAN), the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. We found that c-kit+ progenitor/stem cells accelerated kidney recovery by improving foot process effacement (foot process width was lower in c-kit group vs saline treated animals, P = 0.03). In particular, these cells engrafted in small quantity into tubules, vessels, and glomeruli, where they occasionally differentiated into podocyte-like cells. This effect was related to an up regulation of α-Actinin-4 and mTORC2-Rictor pathway. Activation of autophagy by c-kit+ progenitor/stem cells also contributed to kidney regeneration and intracellular homeostasis (autophagosomes and autophagolysosomes number and LC3A/B-I and LC3A/B-II expression were higher in the c-kit group vs saline treated animals, P = 0.0031 and P = 0.0009, respectively). Taken together, our findings suggest that kidney-derived c-kit+ progenitor/stem cells exert reparative effects on glomerular disease processes through paracrine effects, to a lesser extent differentiation into podocyte-like cells and contribution to maintenance of podocyte cytoskeleton after injury. These findings have clinical implications for cell therapy of glomerular pathobiology.

• Authors: Erika B Rangel, Samirah A Gomes, Rosemeire Kanashiro-Takeuchi, Russell G Saltzman, Changli Wei, Phillip Ruiz, Jochen Reiser, Joshua M Hare
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 14723 (10 03 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30283057 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ACTN4 protein, human
• Actinin
• Puromycin Aminonucleoside
• KIT protein, human
• Proto-Oncogene Proteins c-kit
• Mechanistic Target of Rapamycin Complex 2

Topics

• Actinin (genetics)
• Animals
• Cell Differentiation (genetics)
• Glomerulosclerosis, Focal Segmental (genetics, pathology)
• Humans
• Kidney (metabolism, pathology)
• Kidney Glomerulus (growth & development, metabolism)
• Male
• Mechanistic Target of Rapamycin Complex 2 (genetics)
• Nephrosis, Lipoid
• Podocytes (metabolism)
• Proteinuria (chemically induced, genetics, pathology)
• Proto-Oncogene Proteins c-kit (genetics)
• Puromycin Aminonucleoside (toxicity)
• Rats
• Regeneration (genetics)
• Reperfusion Injury (genetics, pathology)
• Stem Cells (metabolism)