Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3 beta?

Background: Male Irs2(-/-) mice develop fatal type 2 diabetes at 13-14 weeks. Defects in neuronal proliferation, pituitary development and photoreceptor cell survival manifest in Irs2(-/-) mice. We identify retarded renal growth in male and female Irs2(-/-) mice, independent of diabetes.

Jagged/Notch signalling is required for a subset of TGFβ1 responses in human kidney epithelial cells.

The Jagged/Notch pathway has been implicated in TGFß1 responses in epithelial cells in diabetic nephropathy and other fibrotic conditions in vivo. Here, we identify that Jagged/Notch signalling is required for a subset of TGFß1-stimulated gene responses in human kidney epithelial cells in vitro. TGFß1 treatment of HK-2 and RPTEC cells for 24 h increased Jagged1 (a Notch ligand) and Hes1 (a Notch target) mRNA. This response was inhibited by co-incubation with Compound E, an inhibitor of ?-secretase (GSI), an enzyme required for Notch receptor cleavage and transcription regulation. In both cell types, TGFß1-responsive genes associated with epithelial–mesenchymal transition such as E-cadherin and vimentin were also affected by ?-secretase inhibition, but other TGFß1 targets such as connective tissue growth factor (CTGF) and thrombospondin-1 (THBS1) were not. TGFß1-induced changes in Jagged1 expression preceded EMT-associated gene changes, and co-incubation with GSI altered TGFß1-induced changes in cell shape and cytoskeleton. Transfection of cells with the activated, cleaved form of Notch (NICD) triggered decreased expression of E-cadherin in the absence of TGFß1, but did not affect a-smooth muscle actin expression, suggesting differential requirements for Notch signalling within the TGFß1-responsive gene subset. Increased Jagged1 expression upon TGFß1 exposure required Smad3 signalling, and was also regulated by PI3K and ERK. These data suggest that Jagged/Notch signalling is required for a subset of TGFß1-responsive genes, and that complex signalling pathways are involved in the crosstalk between TGFß1 and Notch cascades in kidney epithelia.


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Genetic Polymorphisms in Nitric Oxide Synthase 3 Gene and Implications for Kidney Disease: A Meta-Analysis

Background/Aims: The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes. Methods: We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available. Results: A novel association was identified in the discovery collection (rs1800783, p(genotype) = 0.006, p(allele) = 0.002, OR = 1.26, 95% CI: 1.08-1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r(2) = 0.96 with rs1800783) in the replication collection (p(genotype) = 0.002, p(allele) = 0.0006, OR = 1.27, 95% CI: 1.10-1.45). Conclusion: The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene. Copyright (C) 2010 S. Karger AG, Basel

Protein kinase B/Akt regulation in diabetic kidney disease

Many reviews have been written on protein kinase B/Akt focusing on its history dating back from the isolation of the Akt8 transforming murine leukemia virus by Staal in 1977, to the co-discovery of the Akt1 gene by the three groups in 1991 (reviewed in 7). There are currently over 22,000 publications in the PubMed database with "Akt" as a keyword - these publications describe a wealth of diverse data on the physiological functions of Akt isoforms. Many of these publications describe roles of Akt ranging from its requirement for cellular processes such as glucose uptake, cell survival and angiogenesis to roles in diseases such as cancer and ischaemia (22). This review will focus on the evidence for Akt signaling in different kidney cells during diabetes, or diabetic nephropathy (DN).

Allelic depletion of grem1 attenuates diabetic kidney disease.

OBJECTIVE: Gremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy. RESEARCH DESIGN AND METHODS: Here we explored whether knockout mice heterozygous for grem1 gene deletion (grem1(+/-)) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes. RESULTS: A marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1(+/-) mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1(+/-) and wild-type mice, several indicators of diabetes-associated kidney damage such as increased glomerular basement membrane thickening and microalbuminuria were attenuated in grem1(+/-) mice compared with those in wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wild-type but not in grem1(+/-) kidneys. Levels of pSmad1/5/8 decreased in wild-type but not in grem1(+/-) diabetic kidneys, suggesting that bone morphogenetic protein signaling may be maintained in the absence of grem1. CONCLUSIONS: These data identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease.

Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant

Importance of the field: Tacrolimus is the most commonly used immunosuppressive agent following solid-organ transplantation in children. Its clinical use, however, is complicated by side effects (mainly nephrotoxicity), narrow therapeutic index and pharmacokinetic variability which can result in an increased risk of treatment failure or toxicity. Studies examining inter-individual differences in the expression of the ABCB1 (ATP-binding cassette, subfamily B, member 1) gene (which encodes the drug transporter, P-gp) and its genetic polymorphisms have attempted to elucidate variations in tacrolimus response and disposition in children.