The pathogenesis of diabetic nephropathy

Dronavalli, Suma; Duka, Irena; Bakris, George L.

doi:10.1038/ncpendmet0894

Cited by 539 publications

(428 citation statements)

References 77 publications

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“…2007; Dronavalli et al. 2008). In the present study, the DM rats showed higher daily excretion of albumin and total protein compared with control rats.…”

Section: Discussionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC‐5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24‐h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC‐5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real‐time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC‐5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low‐molecular‐weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

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“…2007; Dronavalli et al. 2008). In the present study, the DM rats showed higher daily excretion of albumin and total protein compared with control rats.…”

Section: Discussionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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“…1,2 As shown in Figure 4, A and B, GBM thickness increased significantly in the diabetic WT mice but did not change in the diabetic TxNIP KO. Similarly, effacement of the podocyte foot processes was observed only in the diabetic WT mice (Figure 4, A and C).…”

Section: Lack Of Txnip Protects Mice From Diabetes-induced Renal Fibrmentioning

confidence: 96%

“…2,30,31 Current attempts to normalize glycemia, control BP, and maintain blockade of the renin-angiotensin system have not eliminated DN or the need for dialysis and/or renal transplantation. 2,30,31 Thus, it is essential to identify novel drug targets and more effective therapy.…”

Section: Discussionmentioning

confidence: 99%

“…These results support our 15 20 Podocyte numbers decline in DN, and this decrease signals progression to advanced disease. 1,2,[21][22][23] Thus, the numbers of podocytes were determined by staining for (Wilms' tumor antigen-1 (WT-1), a transcription factor restricted to podocytes. 24 The podocyte number per glomerulus was determined as described in the Concise Methods section to correct for changes in glomerular volume.…”

Section: Lack Of Txnip Protects Mice From Diabetes-induced Renal Fibrmentioning

confidence: 99%

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Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

Shah

Xia

Masson

et al. 2015

Journal of the American Society of Nephrology

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Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogenactivated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP 2/2 , and TxNIP +/2 mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP 2/2 mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP 2/2 mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-b1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1b mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP 2/2 mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O 2 2 generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.

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“…Oxidative stress plays a causal role in DN62 (Figure 2). The main sources of superoxide in the kidney are the NOX enzymes, specifically the homologs NOX4 and NOX5, the latter only present in humans 63.…”

Section: Diabetic Nephropathy Antioxidant Defences and Immunotherapiesmentioning

confidence: 99%

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

et al. 2018

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Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

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The pathogenesis of diabetic nephropathy

Cited by 539 publications

References 77 publications

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

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