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Nephrology beyond JASN |
So far 10 toll-like receptors (TLR) that recognize distinct pathogen-associated molecular patterns have been reported in mammalian species. TLR represent of family of transmembrane proteins with an extracellular domain rich in leucine repeats and a cytoplasmic Toll/IL-1 receptor homology domain (1,2).
Zhang browsed in the human and mouse genome databases provided by the National Center for Biotechnology Information to assess whether additional TLR beyond the 10 known members can be identified. This search in the mouse led to the recovery of a genomic sequence with an open reading frame encoding a hypothetical 907 amino acid protein with the characteristics of a toll receptor that the authors designated TLR-11. Using the cytoplasmic domain of TLR-11 cDNA as a probe, strong expression was found in the urinary tract (bladder) and kidney as well as liver, whereas expression was low in the spleen and absent in most blood cell types. In contrast, the known TLR-4 is expressed in urinary tract and bladder only but not in kidney (3).
TLR-11 triggers activation of the central molecular inflammatory switches NF-
B and AP-1, as shown with a stably transfected NF-B or AP-1 reporter construct. The search for stimulating agents led to surprising results. The known activating TLR ligands such as lipopolysaccharide, peptidoglycane, and polyinosinic:polycytidylic acid failed to activate NF-B in cells that were transfected with TLR-11, but uropathogenic Escherichia coli, even when heat-killed, were strongly stimulatory, suggesting that uropathogenic E. coli are a ligand for TLR-11. This assumption was corroborated further by the observation that mutant mice lacking TLR-11 were stimulated by lipopolysaccharide, peptidoglycane, and polyinosinic polycytidylic acid but failed to be stimulated by uropathogenic E. coli.
After intraurethral infection with uropathogenic E. coli, bladders were infected both in wild-type and in knockout mice, but the kidneys were infected massively only in the knockout animals. Apparently, absence of TLR-11 rendered mice susceptible to renoparenchymal bacterial infection, leading to the conclusion that the function of TLR-11 is to recognize uropathogenic E. coli and to protect the kidney from ascending infection.
Although this further finding is currently still preliminary, it is also of considerable interest that in the human genome (National Center for Biotechnology Information database), the authors noted that humans seem to fail to express full-length TLR-11 protein. The investigators pointed to the analogy with a stop codon in TLR-5, which renders certain individuals unable to respond to flagellated bacteria (4).
Unless major species differences make extrapolations impossible, the exciting results suggest that this novel member of the Toll receptor family with unique specificities is crucial in the genesis of ascending urinary tract infection.
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Address correspondence to: Prof. Eberhard Ritz, Department Internal Medicine, Division of Nephrology, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany. Phone: 49-0-6221-601705 or 49-0-6221-189976; Fax: 49-0-6221-603302; E-mail: Prof.E.Ritz{at}t-online.de
References
Beyond any doubt in the past two decades, the introduction of erythropoietin (EPO) into the therapeutic armamentarium of the nephrologist has brought about the single most important progress for treatment and rehabilitation of uremic patients. What has been completely unexpected, however, is the recent finding that EPO is not only a renal hormone promoting hematopoiesis but also, presumably as a result of its antiapoptotic properties, at least in extremely high doses, a hormone that protects against parenchymatous organ injury. The spectrum ranges from neuroprotection in various models of central nervous system damage (1) and cerebral infarction in humans (2) to retinal ischemia (3), neuropathic lesions in diabetes (4,5), and experimental myocardial infarction (6).
One dilemma, if one considers transferring the insights from these models to patient treatment, is the predicament that administration of the extremely high doses of EPO required for this purpose will necessarily cause unwanted polyglobuly. One way to circumvent this problem was desialylation of the molecule (7). The resulting asialo-EPO crosses the blood–brain barrier but has an extremely short half-life that mitigates—but certainly does not abrogate—the risk of side effects in the periphery.
This field has been given a new twist by the recent work of Leist et al. (8). They started with the postulate that the homodimeric EPO receptor [(EPOR)2] that mediates the neuroprotective effects of EPO differs from the receptor that mediates the effects on erythropoiesis. They concluded that it therefore should be feasible to construct EPO analogues devoid of stimulatory effects on erythropoiesis. To this end, the lysine molecules in EPO were transformed to homocitrullin by carbamylation, thus altering protein conformation and hopefully function. The resulting product, named carbamylated EPO (CEPO), was inactive in an hematopoiesis bioassay yet was neuroprotective in various in vitro assays and in vivo models of neural damage. CEPO failed to bind at 10,000 pM concentration to cellular models of erythropoiesis expressing the classical receptor, whereas CEPO bound to EPO receptors on neural cells and activated downstream signaling pathways via STAT-5 or Jak2. CEPO was shown to cross readily the blood–brain barrier, yet chronic administration of high doses of CEPO, in contrast to low doses of EPO, failed to increase the hematocrit. The therapeutic potential of this compound is obvious.
The authors deduce from their findings that CEPO engages an alternative receptor that selectively triggers signaling pathways involved in organoprotection. This paradigm will open an entirely new window on organoprotection by EPO.
References
Throughout the world, autosomal dominant polycystic kidney disease (ADPKD) accounts for 5 to 10% of patients who require renal replacement therapy. It therefore is a leading cause of ESRD. It is genetically heterogeneous. The two genes so far identified, PKD1 and PKD2, are thought to interact in renal cells, one major function being regulation of intracellular calcium. Grantham and colleagues (1,2) had postulated that increased cAMP concentrations result from altered intracellular calcium homeostasis and are involved in creating the proliferative and secretory phenotype characterizing cyst wall epithelial cells in contrast with the inhibitory effect of cAMP in the normal kidney cortex. Agonists that increase cellular cAMP, e.g., arginine vasopressin, prostaglandin E2, catecholamines, and cyst-activating factor, a neutral lipid isolated from cyst fluid (3), have the potential to stimulate cyst proliferation and fluid secretion into the cyst. In this context, it is of considerable interest that—in contrast to previous opinion—it is currently thought that the vast majority of the cysts stain for collecting duct markers and are derived from collecting ducts (4), the major target for arginine vasopressin in the nephron. It is also of note that a defect of urinary concentration is one of the earliest manifestations of ADPKD (5).
In previous studies, inhibition of the vasopressin V2 receptor coupling with adenyl cyclase had interfered with formation and growth of cysts. This was seen in experimental models of renal cyst formation that were orthologous to human autosomal recessive PKD and nephronophthisis, respectively (6). The present study (7) carried this one step further by studying an animal model of ADPKD that is even more relevant to the most prevalent form of PKD in humans. The authors investigated Pkd–/tm1Som mice, which are orthologous to PKD2 in humans. In these animals, the molecular machinery of renal cAMP, aquaporin-2, and V2 receptor was upregulated. The V2 receptor antagonist OPC31260was administered in the diet between 3 and 16 wk of age. This agent reduced renal cAMP, aquaporin-2, and the V2 receptors. Of note, however, treated animals also had lower kidney weight, blood urea nitrogen, cyst number, and markers of mitosis and apoptosis. Within the sensitivity of this animal model, no major side effects were noted.
Obviously, at least in this animal model, the vasopressin V2 antagonist interfered with development and progression of ADPKD. V2 antagonists are studied extensively in hyponatremic states (heart failure, liver cirrhosis) and have a relatively good safety profile, presumably because of their high renoselectivity (8). The above experimental findings also make them hot candidates for controlled studies to interfere with the progression of ADPKD in humans.
References
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