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This Month’s Highlights

	Basic Science Articles

Top Basic Science Articles Clinical Science Articles

Calcimimetics Regulate Parathyroid Hormone (PTH) Gene Expression.

Calcimimetics are a new class of drugs that can be used to treat secondary hyperparathyroidism in patients with chronic kidney disease. Calcimimetics bind to the calcium-sensing receptor in the parathyroid gland and reduce PTH secretion and parathyroid cell proliferation. Levi et al. now report that calcimimetics also reduce PTH gene expression in a rat model of uremia. Induction of uremia produced an increase in PTH mRNA levels that was blocked by administration of a calcimimetic. The rate of transcription of the PTH gene was not affected, which indicated that the effect of the calcimimetic was posttranscriptional. Previous studies from the authors have shown that the posttranscriptional regulation of PTH gene expression is mediated by an RNA-binding protein called AUF1. In uremic rats, binding of AUF1 to the PTH mRNA was increased, whereas calcimimetics blocked the increase in AUF1 binding. Although it remains to be shown whether AUF1 mediates the changes in PTH mRNA levels, these studies suggest an additional mechanism by which calcimimetics act to chronically suppress PTH levels. See Levi et al., pages 107–112.

A Gut Hormone Stimulating Food Intake Is Renoprotective.

The polypeptide ghrelin is an important signal stimulating food intake and gastric emptying. It is a stomach-derived secretagogue for growth hormone (GH) and IGF1. Apart from its role in the regulation of food intake and GH secretion, it also improves systolic LV function and heart failure. The paper of Takeda et al. in this issue of JASN adds another twist to the story of non-classic actions by showing that ghrelin also has renoprotective actions in the ischemia/reperfusion model of acute renal failure. This was indicated by serum creatinine and quantitative renal histology. The authors went one step further by showing that this action was independent of the GH/IGF1 axis because it was also seen in insulin receptor substrate 2 (IRS-2) knockout mice. The beneficial effects on renal function were associated with improved endothelium-dependent vasodilatation and increased NO/cGMP formation. The potential clinical implications of these mechanistically exciting findings are currently unclear. See Takeda et al., pages 113–121.

Are Toll-Like Receptors the Connection between Viral Infections and the Initiation or Exacerbation of GN?

Toll-like receptors (TLR) are a hot topic in renal science because they recognize distinct pathogen-associated molecular patterns, such as viral or bacterial DNA, and trigger activation of central molecular inflammatory switches, including immune responses. Different TLR have different effects. In this paper, Pawar and colleagues examine the expression and consequences of activation of TLR7 in MRL/lpr mice with murine SLE. They report increased expression of TLR7 in inflammatory cells and a marked increase in cytokine production with worsening of renal disease when TLR7 is activated. It has long been recognized that several forms of glomerulonephritis and vasculitis are often preceded by viral infections that also exacerbate the disease. The possibility that TLR might provide a molecular explanation for these clinical observations is intriguing and warrants further study. See Pawar et al., pages 141–149.

	Clinical Science Articles

Top Basic Science Articles Clinical Science Articles

 
Extrarenal Manifestations of a Podocyte Disorder.

Podocin is one of a series of podocyte-associated proteins that was discovered after nephrin and, like nephrin, when mutated or absent results in a congenital nephrotic syndrome with progression to renal failure in childhood. The discovery of these podocyte-associated proteins, their association with steroid-resistant nephrotic syndrome and a focal sclerosis–like lesion, and the unraveling of their molecular interactions and functions have recently preoccupied investigators in the area of glomerular disease. However, to date the clinical phenotypes associated with abnormalities in podocyte proteins have been confined to glomerular disease, primarily nephrotic syndrome, and consequences secondary to the renal lesion. In this paper, Frishberg and colleagues identify a series of primary cardiac abnormalities present in 16 of 18 Arab children born with congenital nephrotic syndrome due to a podocin mutation. The findings suggest an important role for podocin in cardiac development, because podocin is expressed in fetal but not adult hearts, and should stimulate a broader search for nonrenal abnormalities in other podocytopathies. See Frishberg et al., pages 227–231.

Chaperones for Misfolded Proteins—Application to Genetic Diseases.

Mis-sense mutations causing misfolded proteins are associated with their accumulation in the endoplasmic reticulum. Degradation of the protein occurs instead of transport to its normal site of function. Chaperones are molecules designed to interact with the misfolded gene products and, as a result of that binding, the protein achieves a more optimal conformation with normalized function. Bernier et al. describe this approach in this issue of JASN using vasopressin 1a (V1a) and V2 receptor antagonists with in vitro and in vivo studies of mis-sense mutations described in X-linked nephrogenic diabetes insipidus. Although these agonists have proven utility in states of ADH excess, using them as chaperones in X-linked diabetes insipidus is a novel approach. Chaperones are not useful for nonsense mutations or deletions where the protein is not translated, but may be a useful approach in a number of genetic diseases associated with mis-sense mutations. See Bernier et al., pages 232–243.

Cytostatin C May Be Better Than Creatinine in Assessing Risk for Cardiovascular Disease in Older Patients with Chronic Kidney Disease.

There is convincing evidence from observational studies that impaired kidney function is a risk factor for a broad array of adverse outcomes beyond the occurrence of end-stage renal disease. Examples of these include all-cause mortality and hospitalization, morbidity and mortality from cardiovascular disease and in surgical patients, and impaired functional status, sleep, and quality of life. Though the current generation of tools to estimate kidney function, including the MDRD and Cockcroft-Gault equations, is more accurate than either serum creatinine or creatinine clearance, a search for better methods to identify impaired kidney function continues. Cystatin C is one candidate to replace creatinine-based estimates of kidney function. The report by Shlipak and his associates in this issue of JASN examines the predictive validity of cystatin C by comparing the strength of the association between this measure of kidney function and mortality to that of the same association with serum creatinine. The authors report increased mortality as the cystatin C quintile increased, which was independent of other risk factors, and this relationship was not observed for quintiles of serum creatinine. While these results don’t mean that we should now measure cystatin C levels to measure kidney function in the elderly, they do provide additional evidence that this biomarker may become a useful tool in stratifying risk associated with impaired kidney function. See Shlipak et al., pages 254–261.

Developing Markers Associated with Tolerant Human Allografts.

Withdrawing immunosuppressant medications to limit toxicity in allograft recipients is desirable, but identifying which patients will tolerate drug withdrawal without negative consequence to the graft remains problematic. In an effort to provide new insight into this issue, Baeten and colleagues evaluated immune profiles in functionally tolerant renal allograft recipients off immunosuppressant medications and compared the results to those found in patients with chronic rejection (CR). The cross-sectional analysis revealed that CD8 T cells from patients with CR expressed a cytotoxicityassociated CD8⁺CD28^– signature, not found in patients tolerant to their allografts. The data suggest that clinical tolerance is associated with suppression of pathologic cytotoxicity. Prospective studies will be required to determine whether serial CD8 cell profiling will identify and differentiate patients at risk for CR from those who will become tolerant after immunosuppression withdrawal. See Baeten et al., pages 294–304.

Related Articles

Ghrelin Improves Renal Function in Mice with Ischemic Acute Renal Failure

Ryo Takeda, Hiroaki Nishimatsu, Etsu Suzuki, Hiroshi Satonaka, Daisuke Nagata, Shigeyoshi Oba, Masataka Sata, Masao Takahashi, Yuji Yamamoto, Yasuo Terauchi, Takashi Kadowaki, Kenji Kangawa, Tadaichi Kitamura, Ryozo Nagai, and Yasunobu Hirata
J. Am. Soc. Nephrol. 2006 17: 113-121. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Articles