Podocyte biology in diabetic nephropathy

Li, J. J.; Kwak, Seung Jae; Jung, Dukyoo; Kim, Jung J.; Yoo, Tae‐Hyun; Ryu, Dong Ryeol; Han, Seung-Hyeok; Choi, Hoon Young; Lee, Jong-Eun; Moon, Sung Jin; Kim, D. K.; Han, Dae Suk; Kang, Shin Wook

doi:10.1038/sj.ki.5002384

Cited by 165 publications

(125 citation statements)

References 90 publications

(99 reference statements)

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“…These data confirm the functional importance of podocytes in the progression of (diabetic) glomerular disease [33] and for the first time demonstrate a pathogenic role of podocyte-derived CXCL12 in (diabetic) glomerulosclerosis. Our finding that adult C57BL/6 and db/db mouse kidneys produce CXCL12 selectively in podocytes and not in any of the other glomerular cell types is consistent with a previous report that described glomerular CXCL12 production in autoimmune-nephritic NZB/NZW F1 mice [28].…”

Section: Discussionsupporting

confidence: 82%

Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes

Sayyed¹,

Hägele²,

Kulkarni³

et al. 2009

Diabetologia

144

106

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Aims/hypothesis Chemokine (C-X-C motif) ligand 12 (CXCL12) (also known as stromal cell-derived factor-1 [SDF-1]-alpha) is a homeostatic chemokine with multiple roles in cell homing, tumour metastasis, angiogenesis and tissue regeneration after acute injuries. However, its role in chronic diseases remains poorly defined, e.g. in chronic glomerular diseases like diabetic glomerulosclerosis. We hypothesised that CXCL12 may have a functional role during the evolution of diabetic glomerulosclerosis, either by assisting glomerular repair or by supporting the maladaptive tissue remodelling in response to hyperglycaemia and glomerular hyperfiltration. Methods To define the functional role of CXCL12 in the progression of glomerular disease, we used the CXCL12-specific inhibitor NOX-A12, an L-enantiomeric RNA oligonucleotide (Spiegelmer). A mouse model of type 2 diabetes (db/db mice) was used. Male db/db mice, uninephrectomised at 6 weeks of age, received subcutaneous injections with a PEGylated form of NOX-A12, nonfunctional control Spiegelmer or vehicle on alternate days from 4 to 6 months of age. Results Immunostaining localised renal CXCL12 production to glomerular podocytes in db/db mice with early or advanced diabetic nephropathy. CXCL12 inhibition significantly reduced the degree of glomerulosclerosis, increased the number of podocytes, prevented the onset of albuminuria and maintained the peritubular vasculature without affecting blood glucose levels, body weight or glomerular macrophage infiltration. Conclusions/interpretation We conclude that podocytes produce CXCL12, which contributes to proteinuria and glomerulosclerosis in our mouse model of type 2 diabetes. This novel pathomechanism provides the first evidence S. G. Sayyed and H. Hägele contributed equally to this study. Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 82%

Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes

Sayyed¹,

Hägele²,

Kulkarni³

et al. 2009

Diabetologia

144

106

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“…In podocytes, diabetes induces hypertrophy, apoptosis, structural changes, and extracellular matrix synthesis. 23 Rac1 is reportedly necessary for the modulation of cell adhesion and motility by fibronectin. We examined Rac1 activation in mouse podocytes.…”

Section: Pathological Effect Of Fgf2 On the Glomerular Cellsmentioning

confidence: 99%

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney

Okamoto

Honda

Doi

et al. 2015

The American Journal of Pathology

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Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genomewide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy. Among diabetes mellitus nephropathy (DN) cases, intractable dysfunction rapidly propagating to end-stage renal disease often accompanies the nephrotic proteinuria phenotype. Our recent study implicated glypican-5 (GPC5) as a susceptible gene for acquired nephrotic syndrome and demonstrated its functional significance by using podocyte-specific knockout mice; a genome-wide association study of DN satisfying the criterion of nephrotic syndrome also clarified GPC5 as the candidate gene [odds ratio 1.45 (95% CI, 1.18e1.79)].

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“…The etiology is multifaceted and caused by the altered composition of the glomerular basement membrane, impairing both size and charge selectivity, 26 podocyte dysfunction, and more. 26,27 We present a number of biomarkers that are derived from this derangement, with a special focus on podocyte markers later on. Cystatin C is a cysteine proteinase inhibitor which is produced by all nucleated cells at a constant rate.…”

Section: Markers Of Increased Glomerular Permeabilitymentioning

confidence: 99%

Urinary biomarkers of diabetic nephropathy

Mehta¹,

Cabrera²,

Upputalla³

et al. 2013

CBF

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Abstract:The fervent search for an early biomarker for diabetic nephropathy is continuing because this entity has become the leading cause of end-stage renal disease in many countries. Novel biomarkers are being described in a high-speed manner. Using urine as a biological source is especially appealing given its ease of collection and its ability to serve as a direct conduit to the site of injury. We begin by briefly discussing the merits and pitfalls of our gold standard of microalbuminuria, and shift quickly to several promising nontraditional protein and messenger (m)RNA biomarkers. The quality of the evidence for using urinary podocyte as a marker will be described. Exploring entire sets of protein in humans in terms of proteomics has been a favorite approach in the last decade because the technology of protein separation and mass spectrometry allows for the unbiased search for new biomarkers. Isolating urinary microRNA may become yet another preferred method because these small, noncoding mRNA that regulate gene expression are particularly stable and apt for biomarker studies. Finally, the latest development is perhaps the study of exosomes, which are nanometer particles derived from the fusion of internal vesicles to the plasma membrane. These particles harbor protein, mRNA, and microRNA that may be isolated for further study. With the advent of newer technologic approaches, we hope that these newly discovered biomarkers will be rigorously tested in large, prospective, clinical trials so they can be implemented in clinical practice.

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Podocyte biology in diabetic nephropathy

Cited by 165 publications

References 90 publications

Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes

Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney

Urinary biomarkers of diabetic nephropathy

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