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Review
. 2021 Mar 24:8:659013.
doi: 10.3389/fmed.2021.659013. eCollection 2021.

Glomerular Endothelial Cell Crosstalk With Podocytes in Diabetic Kidney Disease

Nassim Mahtal  1 , Olivia Lenoir  1 , Pierre-Louis Tharaux  1
Affiliations
Review

Glomerular Endothelial Cell Crosstalk With Podocytes in Diabetic Kidney Disease

Nassim Mahtal et al. Front Med (Lausanne). .

Abstract

Diabetes is the main cause of renal failure worldwide. Complications of the kidney micro-and macro-circulation are common in diabetic patients, leading to proteinuria and can progress to end-stage renal disease. Across the complex interplays aggravating diabetes kidney disease progression, lesions of the glomerular filtration barrier appear crucial. Among its components, glomerular endothelial cells are known to be central safeguards of plasma filtration. An array of evidence has recently pinpointed its intricate relations with podocytes, highly specialized pericytes surrounding glomerular capillaries. During diabetic nephropathy, endothelial cells and podocytes are stressed and damaged. Besides, each can communicate with the other, directly affecting the progression of glomerular injury. Here, we review recent studies showing how in vitro and in vivo studies help to understand pathological endothelial cells-podocytes crosstalk in diabetic kidney disease.

Keywords: angiocrine factors; diabetes; disease module identification; endothelium/physiopathology; glomerulosclerosis; glycocalyx (glycocalix); podocyte.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the GFB during normal (left) and DKD (right) conditions. During DKD, podocytes lose their foot processes, dedifferentiate with transiently increased ANGPT2 and VEGF production, and then detach or die, which then leads to fewer VEGF secretion. Initial and sustained loss of endothelial permselectivity is also fostered by ANGPT2/ANGPT1 imbalance fostering EC lesions through binding to its receptor TIE2. This initially reduces ECs quiescence and impairs permselectivity then ECs viability, and stimulates ET-1 synthesis that in turn acts on the other side of the GFB, activating podocyte Wnt/beta-catenin and NFkB pathways, heparanase release, inappropriate cytoskeletal remodeling, and abnormal extracellular matrix synthesis causing GBM thickening. ET-1 produced by EC but also by podocytes may also contribute to increased oxidative stress and secretion of proteases, which can degrade the glycocalyx, creating a vicious loop. Hence, ECs are subjected to oxidative and mitochondrial stress, lose their fenestrations, do not exert their functions properly, and may die. Deleterious effects of (ECs-derived?) -TGFβ-mediated signaling on podocytes are suggested. Moreover, the overproduction of sulfatases in the GBM could decrease the bioavailability of growth factors needed by ECs. The GBM thickens due to extracellular matrix (ECM) protein deposits, such as collagen fibers and fibronectin which augments the distance between rarefied podocytes and ECs, potentially altering podocyte to EC bidirectional signal cross-talk.
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