Expression of human nephrin mRNA in diabetic nephropathy

Toyoda, Masao; Suzuki, Daisuke; Umezono, Tomoya; Uehara, Goro; Maruyama, Masaki; Honma, Masashi; Sakai, Takako; Sakai, Hideto

doi:10.1093/ndt/gfg545

Cited by 64 publications

(53 citation statements)

References 18 publications

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“…In addition, during the experimental period, major urinary protein was detected in all mice, as reported (19). Alterations in the level of nephrin expression have also been documented in a variety of acquired renal diseases that include diabetic nephropathy and minimal change nephropathy (8,30). Thus, using this sepsis-induced albuminuric model, we evaluated nephrin expression at the albuminuric stage (i.e.…”

Section: Methodsmentioning

confidence: 88%

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

2010

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Sepsis is induced by infectious challenges, and septic organ failure often occurs under local and systemic inflammation. Albuminuria is also evident during sepsis, but little is known about the molecular basis of septic albuminuria. Using lipopolysaccharide (LPS)-treated mice as a sepsis model, we found that the loss of nephrin, a key component for maintaining podocyte slit diaphragm, became evident in accordance with the onset of albuminuria, especially 36 h post-LPS challenge (i.e., albumiuric stage). Likewise, nephrin mRNA levels were decreased to 13% of saline-treated mice. Such a transcriptional suppression of nephrin was associated with the loss of nucleus-localized Wilms tumor-1 (WT1), a transcriptional factor for up-regulating nephrin gene. Thereafter, urinary albumin levels were decreased in mice between 72 and 96 h post-LPS challenge (i.e., recovery-stage). Notably, nuclear localization of WT1 seemed to be normalized, and nephrin mRNA and protein levels returned near the basal level 72 h post-LPS challenge. During LPS-mediated sepsis, there was a transient increase in blood interleukin-1β, a suppressor of nephrin production in podocytes. Therefore, down-regulation of nephrin by the loss in nuclear WT1, along with hyper-cytokinemia, may underlie the mechanisms by which albuminuria is induced by infectious stresses.Septic syndrome is elicited by infectious agents of bacteria, virus, and fungus. The infectious components (including bacterial cell walls) function as foreign ligands of toll-like receptors, and systemic inflammation elicits thrombosis and eventually multiple organ failure (4, 26). Furthermore, albuminuria is also a common event during septic diseases (6,25,28), along with inflammatory responses. For example, lipopolysaccharide (LPS) of Escherichia coli, or histone-like protein of Streptococcal pyogenesis, often triggers albuminuria and glomerular nephritis (1,32,33), and this is associated with over-production of pro-inflammatory cytokines by activated macrophages (10,22). However, it is still unclear how sepsis-induced albuminuria is linked with an increase in pro-inflammatory cytokines (i.e., cytokine storm). Recent merging evidences provide a central dogma that glomerular podocytes have a key function to prevent the onset of albuminuria (2, 16, 31). Podocytes form foot processes, highly dynamic cellular extensions that are connected by slit diaphragm. As an important protein for podocytes, nephrin (encoded by NPHS1 gene) is well known (16,31). Nephrin is a transmembrane protein of the

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Section: Methodsmentioning

confidence: 88%

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

2010

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“…For example, maintenance of normal expression of nephrin and other proteins that are essential for the integrity of the slit diaphragm (33)(34)(35) may explain why AER is not elevated in the setting of a microscopic glomerulopathy. In contrast, a reduced GFR may be associated with pathological changes, including, but not exclusively related to, morphological changes that result in an increase in intrarenal vascular disease.…”

Section: The Effect Of Ras Inhibition On Intrarenal Resistance Indexmentioning

confidence: 99%

Is Nonalbuminuric Renal Insufficiency in Type 2 Diabetes Related to an Increase in Intrarenal Vascular Disease?

et al. 2006

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OBJECTIVE -To investigate the role of intrarenal vascular disease in the pathogenesis of nonalbuminuric renal insufficiency in type 2 diabetes.RESEARCH DESIGN AND METHODS -We studied 325 unselected clinic patients who had sufficient clinical and biochemical information to calculate an estimated glomerular filtration rate (eGFR) using the Modified Diet in Renal Disease six-variable formula, at least two estimations of urinary albumin excretion rates (AER), and a renal duplex scan to estimate the resistance index of the interlobar renal arteries. The resistance index, measured as part of a complications surveillance program, was compared in patients with an eGFR Ͻ or Ն60 ml/min per 1.73 m 2 who were further stratified into normo-(AER Ͻ20), micro-(20 -200), or macroalbuminuria (Ͼ 200 g/min) categories.RESULTS -Patients with an eGFR Ͻ60 ml/min per 1.73 m 2 had a higher resistance index of the renal interlobar arteries compared with patients with an eGFR Ն60 ml/min per 1.73 m 2 . However, the resistance index was elevated to a similar extent in patients with an eGFR Ͻ60 ml/min per 1.73 m 2 regardless of albuminuric status (normo-0.74 Ϯ 0.01, micro-0.73 Ϯ 0.01, and macroalbuminuria resistance index 0.75 Ϯ 0.11). Multiple regression analysis revealed that increased age (P Ͻ 0.0001), elevated BMI (P ϭ 0.0001), decreased eGFR (P Ͻ 0.01), and decreased diastolic blood pressure (P Ͻ 0.01), but not an increased AER, were independently associated with an elevated resistance index in patients with impaired renal function.CONCLUSIONS -Subjects with type 2 diabetes and reduced glomerular filtration rate had similar degrees of intrarenal vascular disease, as measured by the intrarenal arterial resistance index, regardless of their AER status. The pathological mechanisms that determine the relationship between impaired renal function and AER status in subjects with type 2 diabetes remain to be elucidated. Diabetes Care 29:1560 -1566, 2006T raditionally, microvascular disease resulting in a glomerulopathy and an increase in albumin excretion rate (AER) is believed to be the only significant mechanism by which diabetic renal disease develops. However, recent results have challenged the concept that a decline in renal function in patients with diabetes is always accompanied by an increased AER. Results from our group (1,2) and from the Third National Health and Nutrition Survey (NHANES III) (3,4) have suggested that the finding of nonalbuminuric renal insufficiency is not an uncommon discovery for subjects with diabetes, especially those with type 2 diabetes.The structural basis of nonalbuminuric renal insufficiency in type 2 diabetes remains to be elucidated. However, the use of techniques such as duplex Doppler ultrasound allows for the rapid, noninvasive evaluation of the intrarenal vasculature (5). In particular, the presence of intrarenal vascular disease can be documented by the use of established methods such as the calculation of the resistance index (5,6). Intrarenal arteriosclerosis, as opposed to other forms of renal dama...

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“…10,11 Experiments that were designed to demonstrate a relationship between changes in nephrin expression and/or localization and proteinuria in various forms of glomerular diseases, including DN, have been inconsistent. [12][13][14][15][16][17][18][19] A reduction in nephrin expression has been observed in experimental glomerular diseases 12 and in adult patients with primary acquired nephrotic syndrome 15 but not in pediatric patients with glomerular diseases. 16 In cases of experimental DN, one study demonstrated a reduction in nephrin mRNA and protein expressions in streptozotocin-induced diabetic spontaneously hypertensive rats, 14 whereas another study in streptozotocin-induced diabetic rats and in nonobese diabetic mice revealed an increase in nephrin mRNA levels.…”

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confidence: 99%

Differential Expression of Nephrin According to Glomerular Size in Early Diabetic Kidney Disease

Kim

Jung

et al. 2007

Journal of the American Society of Nephrology

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Diabetic nephropathy (DN) is clinically characterized by proteinuria. Many studies tried to demonstrate a relationship between proteinuria and changes in nephrin in various forms of glomerular diseases including DN, but the results are not consistent. Glomerular hypertrophy occurs in DN, yet hypertrophy does not develop in all glomeruli concurrently. For investigation of the differences in nephrin expression according to glomerular size, glomeruli were isolated from 10 control and 10 streptozotocin-induced diabetic rats at 6 wk after the induction of diabetes by a sieving technique using sieves with pore sizes of 250, 150, 125, and 75 m. Glomeruli then were classified into large glomeruli (LG; on the 125-m sieve) and small glomeruli (SG; on the 75-m sieve) groups. Glomerular volumes were determined using an image analyzer, and mRNA and protein expression was determined by real-time PCR and Western blot, respectively. The mean volumes of diabetic LG (1.51 Ϯ 0.06 ϫ 10 6 m 3 ) and control LG (1.37 Ϯ 0.05 ϫ 10 6 m 3 ) were significantly higher than those of diabetic SG (0.94 Ϯ 0.03 ϫ 10 6 m 3 ) and control SG (0.87 Ϯ 0.03 ϫ 10 6 m 3 ; P Ͻ 0.01). Nephrin mRNA expression was significantly reduced in the diabetic LG group compared with the diabetic SG and control glomeruli groups (P Ͻ 0.05). In contrast, nephrin mRNA expression was significantly higher in the diabetic SG group compared with the diabetic LG and control glomeruli groups (P Ͻ 0.05). Even after correction for 18s rRNA and Wilms' tumor-1 mRNA expression, the differences in nephrin mRNA expression remained significant. The expression of nephrin protein showed a similar pattern to the mRNA expression. In conclusion, these data suggest that the nephrin gene is differentially expressed according to glomerular size. Furthermore, more hypertrophied glomeruli with lesser nephrin expression may be responsible for albuminuria in the early stage of DN.

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Expression of human nephrin mRNA in diabetic nephropathy

Abstract: The low expression of nephrin mRNA may be closely linked to development and/or progression of proteinuria in human diabetic nephropathy.

Cited by 64 publications

References 18 publications

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

Is Nonalbuminuric Renal Insufficiency in Type 2 Diabetes Related to an Increase in Intrarenal Vascular Disease?

Differential Expression of Nephrin According to Glomerular Size in Early Diabetic Kidney Disease

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