Basic Science Articles
Polycystin-1 Activates PI3 Kinase/AKT Signaling.
Expression of polycystin-1 in MDCK cells promotes tubulogenesis and confers resistance to apoptosis. Boca et al. examined the mechanism underlying these effects. They found that expression of wild-type polycystin-1, but not mutant polycystin-1, activates phosphatidylinositol 3-kinase (PI3-kinase) and stimulates the phosphorylation of Akt (protein kinase B) and its downstream target FKRH-1. Akt has previously been shown to stimulate tubulogenesis and inhibit apoptosis. Expression of a dominant-negative Akt mutant prevents the resistance to apoptosis conferred by polycystin-1. Treatment with PI3-kinase inhibitors blocks phosphorylation of Akt and inhibits tubulogenesis. Recent studies suggest that inhibition of calcium-dependent activation of PI3-kinase and Akt leads to activation of ERK kinases and increases cell proliferation. Taken together, these findings suggest that polycystin-1 may exert its cellular effects by promoting calcium entry and activating the PI3-kinase/Akt signaling pathway. In autosomal dominant polycystic kidney disease, loss of polycystin-1 results in inhibition of PI3-kinase/Akt, increased ERK, and increased proliferation and apoptosis. See Boca et al., pages 637–647.
A Way to Protect the Kidney from Injury Induced by Lithotripsy.
It is well established that in lithotripsy shock waves of sufficient intensity to disrupt stones also induce significant renal injury and some loss of function. Several years ago, Willis et al. reported that application of a therapeutic dose of shock waves to one pole of the kidney seemed to protect the opposite pole from injury when it was treated with the same dose later. In this study, these observations are extended to show that this protective effect is reproducible, that protection can be conferred by lower doses of shock waves that do not induce injury, and that protective doses can be applied prophylactically to the same area later treated with higher therapeutic doses. The study does not define the mechanism of the protective effect, but it offers an excellent model in which to do that and suggests that lithotripsy can likely be made a much safer and less injurious procedure than it currently is. See Willis et al., pages 663–673.
Regulatory T Cells Limit Proteinuric Renal Injury in Mice.
The pathogenesis of adriamycin nephropathy, a murine model of chronic proteinuric renal disease, involves both chemical and immunologic mechanisms. Published studies have implicated T lymphocytes as contributing to the development of this disease. To assess whether regulatory T cells could prevent adriamycin nephropathy, Wang et al. transduced CD4+ T cells with Foxp3, a transcription factor that is considered the “master switch” for induction of a regulatory T cell phenotype. The authors demonstrated that Foxp3-transduced T cells, but not controls, indeed exhibited features of regulatory/suppressor T cells. Moreover, adoptive transfer of the ex vivo–transduced regulatory T cells limited the functional and histologic manifestations of adriamycin nephropathy. This novel effect of Foxp3-transduced regulatory T cells on the development of chronic renal disease has potentially important therapeutic implications. See Wang et al., pages 697–706.
How Is the Glomerulus Vascularized?
Vascular endothelial growth factor (VEGF) is a secreted protein that stimulates angiogenesis. During normal kidney development, VEGF produced by developing podocytes is required for the migration of endothelial cells into the glomerulus. Eremina et al. now show that VEGF is also required for mesangial cell migration and survival. Mice expressing a hypomorphic allele of VEGF are born with normal glomeruli but undergo mesangiolysis within 10 to 12 d after birth. Mesangiolysis is preceded by the loss of glomerular endothelial cells. The complete absence of VEGF in podocytes prevents the migration of mesangial cells into developing glomeruli. Mesangial cells do not express VEGF receptors, but they do express receptors for PDGF, a growth factor produced by endothelial cells. These findings suggest that the vascularization of the developing glomerulus proceeds via a two-step process in which VEGF produced by podocytes stimulates endothelial cell migration, then PDGF produced by glomerular endothelial cells stimulates mesangial cell migration. See Eremina et al., pages 724–735.
Clinical Science Articles
VEGF Gene Polymorphisms Associated with ESRD.
Doi et al. examine polymorphisms of the vascular endothelial growth factor (VEGF) gene in 101 male subjects with ESRD and 189 healthy controls in this issue of JASN. They found that two single nucleotide polymorphisms in the 3′ untranslated region of the gene are linked to each other and are significantly associated with ESRD. Sequence variation in the 3′ untranslated region of a gene does not affect the protein sequence but can affect mRNA stability. The VEGF gene polymorphisms are associated with higher circulating VEGF levels, which appear to be due to increased mRNA stability. Interestingly, overexpression of VEGF in mice (though to a much greater degree than observed in this study) results in a glomerular lesion similar to collapsing glomerulonephritis. Although the findings need to be confirmed in a larger prospective study, this study is the first to suggest that sequence variation in VEGF may be associated with the risk of ESRD in males. See Doi et al., pages 823–830.
Does Preeclampsia Increase the Risk for Later Kidney Disease?
Preeclampsia is associated with increased risk of adverse maternal outcomes, including hypertension, cardiovascular disease, and persistent microalbuminuria. The report by Vikse and colleagues in this issue of JASN suggests that the kidney may not be spared the long-term consequences of this disease. They linked >750,000 women in two national registries to identify women with and without preeclampsia who underwent a subsequent kidney biopsy. They report that both preeclamsia and having an infant with low birth weight were independent risk factors for subsequent kidney biopsy during the next five years. Although the possibility that both the preeclampsia and subsequent kidney biopsy were due to unrecognized kidney disease cannot be totally excluded, these results emphasize the need to carefully exclude subclinical kidney disease among women presenting with antepartum hypertension and proteinuria both at initial evaluation and during subsequent follow-up. See Vikse et al., pages 837–845.
Toward Optimal Dosing of Mycophenolic Acid.
Mycophenolic acid (MPA) is an immunosuppressant commonly used to prevent renal transplant rejection. Large between- and within-patient variability in the pharmacokinetics of MPA has been described, but this variability remains largely unexplained. In a retrospective meta-analysis of 468 renal transplant patients from 6 clinical trials, van Hest and colleagues explored the relationship between various clinical factors and the pharmacokinetics of MPA. The study revealed that exposure to MPA independently increased with increasing renal function, albumin, and hemoglobin as well as decreasing prednisone and cyclosporine levels, but was not independently influenced by delayed graft function, recipient race, or diabetes. The findings have clinical relevance in that a significant change in renal function or serum albumin could be used as an indication for therapeutic monitoring of MPA levels, in an effort to maximize efficacy and limit toxicity. See van Hest et al., pages 871–880.
Should All Transplant Recipients Receive ACE/ARB Therapy?
The beneficial effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in reducing proteinuria, slowing progression, and reducing the risk for associated cardiovascular disease is well established in chronic kidney disease patients at high risk for cardiovascular disease. Similar data are not available for transplant recipients who also have chronic kidney disease. This retrospective study of 2031 patients from Austria looked at the effect of ACEI/ARB therapy on graft and patient survival in recipients of renal allografts, adjusting for other risk factors. Heinze et al. report a 20% higher 10-yr patient and graft survival rate in patients treated with ACEI/ARB therapy compared with those who were not. Although the study is retrospective and several important variables are not completely excluded as contributing to the findings, the magnitude of the differences observed are impressive and supports the use of these agents in transplant recipients until the results of prospective trials are available. See Heinze et al., pages 889–899.
- © 2006 American Society of Nephrology
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