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

Abstract

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

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

“…In patients with type 1 diabetes, we have focused on the effect of acute hyperglycaemia on the urinary excretion of cytokines/chemokines rather than tissue expression of these factors, hypothesising that urinary excretion of inflammatory mediators correlates with tissue expression. Similar to observations made in animal studies, we demonstrated that acute hyperglycaemia influences urinary cytokine/chemokine excretion, suggesting that the link between intraglomerular pressure, inflammation and renal injury also exists in humans [1][2][3]6]. From a more clinical perspective, we have demonstrated that increased urinary cytokine/chemokine excretion precedes the onset of early clinical manifestations of nephropathy, including microalbuminuria, in young patients with type 1 diabetes [7].…”

“…Experimental data have suggested the association of high intraglomerular pressure with increased shear stress in diabetes, leading to renal injury [1][2][3]. The pathogenesis of hyperfiltration remains controversial; both haemodynamic (the 'haemodynamic hypothesis') and tubuloglomerular feedback mechanisms (the 'tubular hypothesis') have been implicated [24].…”

“…In experimental models, this is in part a result of hyperglycaemia-induced neurohormonal activation, which increases intraglomerular pressure and shear stress, leading to renal inflammation [1][2][3]. In in vitro studies of human mesangial cells, hyperglycaemia increases the mRNA expression of monocyte chemoattractant protein (MCP-1, also known as CCL2) and vascular endothelial growth factor, which have been linked to cell apoptosis, compensatory hypertrophy and hyperfiltration in animal models of diabetes mellitus [4,5].…”

Polyetheylenimine-Polyplexes of Spiegelmer NOX-A50 Directed against Intracellular High Mobility Group Protein A1 (HMGA1) Reduce Tumor Growth in Vivo

“…Spiegelmer antagonists to a number of extracellular targets have been described (11,14,24,35). Two Spiegelmers have proven to be safe and well tolerated in Phase I clinical studies 4 providing evidence that the Spiegelmer technology is suitable to generate human medicines.…”

“…Spiegelmers (German: Spiegel ϭ mirror) are structured biostable L-oligonucleotides that differ from their aptamer counterparts in their sugar moiety, which consists of mirrorimage L-(deoxy)ribose rather than D-(deoxy)ribose and makes Spiegelmers highly resistant to nucleases (11,12). Spiegelmers have already been described to act potently as inhibitors in vivo (13)(14)(15) and have proven to be exceptionally safe in two Phase I clinical studies. 4 Here, we report the generation of a Spiegelmer, binding to HMGA1 with high affinity.…”