Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

Abstract

Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100–1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes. The purpose of the present study was to examine the role of podocyte MPs in tubular epithelial cell fibrotic responses. MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured human proximal tubule epithelial cells (PTECs). Treatment with podocyte MPs increased p38 and Smad3 phosphorylation and expression of the extracellular matrix (ECM) proteins fibronectin and collagen type IV. MP-induced responses were attenuated by co-treatment with the p38 inhibitor SB202190. A transforming growth factor beta (TGF-β) receptor inhibitor (LY2109761) blocked MP-induced Smad3 phosphorylation and ECM protein expression but not p38 phosphorylation suggesting that these responses occurred downstream of p38. Finally, blockade of the class B scavenger receptor CD36 completely abrogated MP-mediated p38 phosphorylation, downstream Smad3 activation and fibronectin/collagen type IV induction. Taken together our results suggest that podocyte MPs interact with proximal tubule cells and induce pro-fibrotic responses. Such interactions may contribute to the development of tubular fibrosis in glomerular disease.

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…At the molecular level, the mechanisms that activate stress-induced EV biogenesis in the kidney seem to be multifactorial, as EV release cannot be directly induced by specific stress effectors, such as angiotensin II or TGF-β, alone [241]. Podocyte-derived EVs fuse with proximal tubular epithelial cells, inducing phosphorylation of P38 and SMAD3, expression of extracellular matrix proteins, such as fibronectin and collagen type IV, and consequent tubular fibrosis, which contributes to loss of renal functions [242].…”

New insight into the role of extracellular vesicles in kidney disease

“…MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured PTECs. Treatment with podocyte MPs promoted proximal tubule fibrotic signalling via p38 MAPK and CD36 . However, in this study, MPs were from the normal podocyte, it is still unclear what are the effects of MPs from injured podocytes on tubular epithelial cells.…”

Acute and chronic glomerular damage is associated with reduced CD133 expression in urinary extracellular vesicles

“…Furthermore, the increase of water flow in recipient cells proved the functional transfer of AQP2 from EVs deriving from collecting ducts (26). During glomerular disease such as diabetes, podocyte-derived EVs may promote fibrosis of tubular cells, via detrimental glomerular-tubular signals (24). These data suggest that uEVs may orchestrate the trafficking of different renal messages occurring during physiological or pathologic conditions.…”