Nephrin Expression Is Reduced in Human Diabetic Nephropathy

Doublier, Sophie; Salvidio, Gennaro; Lupia, Enrico; Ruotsalainen, Vesa; Verzola, Daniela; Deferrari, Giacomo; Camussi, Giovanni

doi:10.2337/diabetes.52.4.1023

Cited by 321 publications

(287 citation statements)

References 46 publications

Supporting

Mentioning

257

Contrasting

Unclassified

Order By: Relevance

“…Nephrin has also been associated with diabetic nephropathy, with reduced nephrin levels in human biopsies from patients with diabetes and proteinuria [12]. It has been proposed that this contributes to the development of nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…An early marker of this state is microalbuminuria. There is now good evidence that glomerular podocytes are directly targeted in diabetic nephropathy with loss of podocytes into the urine [11] and reduced production of the key podocyte protein nephrin [12]. These phenomena may be mechanisms that lead to disruption of the glomerular filtration barrier and to disease progression in diabetic nephropathy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR) γ agonists are used increasingly in the treatment of type 2 diabetes. In the context of renal disease, PPARγ agonists reduce microalbuminuria in diabetic nephropathy; however, the mechanisms underlying this effect are unknown. Glomerular podocytes are newly characterised insulin-sensitive cells and there is good evidence that they are targeted in diabetic nephropathy. In this study we investigated the functional and molecular effects of the PPARγ agonist rosiglitazone on human podocytes. Methods Conditionally immortalised human podocytes were cultured with rosiglitazone and functional effects were measured with glucose-uptake assays. The effect of rosiglitazone on glucose uptake was also measured in 3T3-L1 adipocytes, nephrin-deficient podocytes, human glomerular endothelial cells, proximal tubular cells and podocytes treated with the NEFA palmitate. The role of the glucose transporter GLUT1 was investigated with immunofluorescence and small interfering RNA knockdown and the plasma membrane expression of GLUT1 was determined with bis-mannose photolabelling. Results Rosiglitazone significantly increased glucose uptake in wild-type podocytes and this was associated with translocation of GLUT1 to the plasma membrane. This effect was blocked with GLUT1 small interfering RNA. Nephrin-deficient podocytes, glomerular endothelial cells and proximal tubular cells did not increase glucose uptake in response to either insulin or rosiglitazone. Furthermore, rosiglitazone significantly increased basal and insulinstimulated glucose uptake when podocytes were treated with the NEFA palmitate. Conclusions/interpretation In conclusion, rosiglitazone has a direct and protective effect on glucose uptake in wild-type human podocytes. This represents a novel mechanism by which PPARγ agonists may improve podocyte function in diabetic nephropathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

et al. 2009

View full text Add to dashboard Cite

show abstract

“…In cultured mesangial cells, Ang II [35][36][37] and aldosterone 38,39 provoke synthesis of extracellular matrix (ECM) proteins that accumulate in glomerulosclerosis. In podocytes, Ang II has been shown to induce apoptosis, 40,41 cytoskeletal rearrangement 42 and nephrin loss 43 in podocytes, alterations that have been linked to albuminuria. 44 Aldosterone can also damage podocytes by inducing apoptosis and reducing nephrin gene expression.…”

Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

View full text Add to dashboard Cite

The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

show abstract

“…Glomerular nephrin mRNA was decreased in biopsies of type 2 diabetic patients who had proteinuria, while the results were similar to those in control subjects when the ACE inhibitor perindopril was used [26]. Another study demonstrated a similar reduction in nephrin protein with altered cellular distribution in biopsies of type 1 and type 2 diabetic patients with the nephrotic syndrome [27]. A particularly interesting finding in that study was that angiotensin II caused the excretion of a 100-kDa protein from the glomerular epithelial cells [27].…”

Section: Discussionmentioning

confidence: 62%

“…Another study demonstrated a similar reduction in nephrin protein with altered cellular distribution in biopsies of type 1 and type 2 diabetic patients with the nephrotic syndrome [27]. A particularly interesting finding in that study was that angiotensin II caused the excretion of a 100-kDa protein from the glomerular epithelial cells [27]. This protein was detectable with an anti-nephrin antibody, and the excretion phenomenon may have involved cytoskeletal rearrangement.…”

Section: Discussionmentioning

confidence: 71%

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: One-third of normoalbuminuric type 1 diabetic patients show immunoreactive nephrin in urine. Offspring of type 2 diabetic patients are insulinresistant and susceptible to the development of diabetes. We investigated whether the offspring of type 2 diabetic patients show nephrin in urine and whether possible nephrinuria is associated with insulin resistance. Methods: : Urinary proteins from timed overnight urine collections from 128 offspring of type 2 diabetic patients and 9 control subjects were analysed by western blotting using an antibody against nephrin. Glucose metabolism was assessed by OGTT and IVGTT and the euglycaemic-hyperinsulinaemic clamp technique. Results: Of the offspring, 12.5% were strongly and 14.1% weakly positive for a 100-kDa urinary protein. All controls were negative. During the first 10 min of an IVGTT, the offspring strongly positive for the urinary protein had a higher inysulin response than the offspring without the protein (3,700 vs 2,306 pmol l −1 min −1 , p=0.007). Insulin sensitivity (the rate of wholebody glucose uptake divided by the steady-state insulin level×100) was lower among the offspring strongly positive for the urinary protein than among the offspring negative for the protein (11.3 vs 15.8 μmol kg −1 min −1 pmol −1 l −1 , p=0.008). Conclusions/interpretation: A 100-kDa urinary protein detectable with a nephrin antibody is associated with insulin resistance in offspring of type 2 diabetic patients.

show abstract

Nephrin Expression Is Reduced in Human Diabetic Nephropathy

Cited by 321 publications

References 46 publications

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients

Contact Info

Product

Resources

About