Glomerular Endothelial Cell Stress and Cross-Talk With Podocytes in Early Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is one of the major causes of morbidity and mortality in diabetic patients and also the leading single cause of end-stage renal disease in the United States. A large proportion of diabetic patients develop DKD and others don’t, even with comparable blood glucose levels, indicating a significant genetic component of disease susceptibility. The glomerulus is the primary site of diabetic injury in the kidney, glomerular hypertrophy and podocyte depletion are glomerular hallmarks of progressive DKD, and the degree of podocyte loss correlates with severity of the disease. We know that chronic hyperglycemia contributes to both microvascular and macrovascular complications, as well as podocyte injury. We are beginning to understand the role of glomerular endothelial injury, as well as the involvement of reactive oxygen species and mitochondrial stress, which play a direct role in DKD and in other diabetic complications. There is, however, a gap in our knowledge that links genetic susceptibility to early molecular mechanisms and proteinuria in DKD. Emerging research that explores glomerular cell’s specific responses to diabetes and cell cross-talk will provide mechanistic clues that underlie DKD and provide novel avenues for therapeutic intervention.

Assessment of 8-Hydroxy-2-Deoxyguanosine (8-OHdG) as a Diagnostic Marker for Diabetic Nephropathy in Type 1 Egyptian Diabetic Patients

“…Also, highly significant increase in diabetic groups with albuminuria (G3 and G4) compared with normoalbuminuria (G2), which has significant increase compared with control group (G1) (p value<0.05). This slightly significant increase in 8-OHdG with type 1 diabetic patients with normoalbuminuria compared with healthy subjects (control) indicated that type 1 causes damage (oxidation) to DNA of kidney cells before occurrence of albuminuria (nephropathy) and after occurance of albuminuria this increase in 8-OHdG is highly increased as indicated between macroalbuminuria (G4) compared with microalbuminuria (G3) and presence of highly significant positive correlation between AER and 8-OHdG in study groups (p value<0.05) .These results are in accordance with Ilse, 2018 and Qi H et al [3,13], they showed oxidative damage increase in endothelial cells of glomerulus detected in patients diagnosed with diabetic kidney disease (DKD), as oxidized DNA lesion excretion in the urine (8-OHdG) was significantly increased in patients with diabetic nephropathy progression, this is disagree with our results as they reported that this increase in 8-OhdG is only diabetic nephropathy progression and not with normoalbuminuria, but they estimated 8-OHdG in urine and we estimated it in serum, so we need more studies in this point and estimate 8-OHdG in both urine and serum samples together and correlate between them and confirm that this significant increase in patients with normoalbuminuria compared with healthy subjects founded in 8-OHdG results in serum, also found in urine or increase only in serum. Sanchez et al and Santosh et al [14,15] were also in agreement with our data, as higher concentrations of 8-OHdG were found to be associated with increased risk of progression of kidney disease in both T1DM and T2DM.…”

“…8-OHdG produced by oxidation of hydroxyl radical (OH•) to carbon in position 8 in amino acid guanine. 8-OHdG reflects general cellular oxidative stress, so it may consider marker of DNA damage in diabetic patients [3]. The most characteristic marker of DN is albuminuria, which is associated with renal disease progression.…”

Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells

“…20 To better understand the mechanism for ESL degradation, we examined the expression of Figure S5). In short, a denser ESL corresponds to a greater 50% effective dose (ED 50 ) value (see Methods for ED 50 (Figure 6a and b). These findings correlate with a decrease of HS and IB4 on mGEC cell surface after Edn1 or DoxSN treatment compared with untreated control or CtrlSN GECs, respectively (Figure 6c and d).…”

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

“…More detailed discussion on the crosstalk between the different renal cell types is beyond the scope of this review, but the given examples underscore the complexity of the regulation of the glomerular filtration and emphasize the role of all glomerular cell types in maintaining the normal kidney function, as well as in contributing to the dysfunction of the filtration barrier in renal diseases, including DKD. The topic of glomerular cell crosstalk has been extensively covered by several recent reviews …”