Adult mouse kidney stem cell‐derived exosomes navigate nephron repair and regeneration in aged mice

Abstract

The physiological function of kidney stem cell‐derived extracellular vesicles remains elusive. Most recently, we isolated kidney stem cells (KSCs) from adult mouse kidneys and demonstrated that KSCs‐derived exosomes normalized blood pressure and improved kidney functions in hypertensive aged mice. To study if KSCs‐derived exosomes play a role in nephron repair and regeneration, we treated aged mice with CD63‐GFP labelled KSC‐exosome (CD63/GFP KSC‐Exo) (~1.0×1011particles/mouse) and traced CD63/GFP KSC‐Exo in the kidney. We found that KSC‐exosomes were mainly detected in the proximal and distal tubular cells near the damaged glomerulus in cortex area of the aging kidney. BrdU tracing study showed that BrdU positive cells were mainly detected in the glomerulus and co‐located with Ki67 cell proliferation marker in the kidney of KSC‐exosome treated mice. KSC‐exosome treatment also increased numbers of Sca1+cells surrounding the glomerulus area of aging kidney. Interestingly, the glomerular filtration rate (GFR) was significantly increased in KSC‐exosome‐treated aged mice, suggesting improved glomerular function. To explore the mechanisms how KSC‐exosome improves kidney functions, we performed proteome analysis of KSC‐exosomes by mass spectrometry. We found several pathways that involve in the kidney development were upregulated in the KSC‐exosome from adult mice compared to that of aged mice. Notably, we further identified that FBLN2, an extracellular matrix protein, plays an important role in aging‐associated hypertension. We showed that expression of FBLN2 was downregulated in the kidney of aged mice and recombinant FBLN2 (rFBLN2) treatment normalized blood pressure and improved GFR of hypertensive aged mice. Furthermore, we found that FBLN2 is mainly located in the basement membrane of glomerulus (GBM). The thickness of GBM was increased in aged mice determined by TEM. KSC‐exosome or rFBLN2 treatment reduced the thickness of GBM, suggesting that FBLN2 may play an important role in maintaining the integrity of GBM and kidney functions. In conclusion, our finding provided the first evidence that the adult mouse kidney stem cell‐derived exosomes play an important role in nephron repair and regeneration partly via FBLN2. KSC‐exosome treatment may be a novel therapeutic strategy for hypertension‐associated kidney injuries in aging.