Kidney cancer
To date, the role of Trp metabolites in carcinogenesis has not been unequivocally established. There are only a few studies linking the KYN pathway with kidney cancer. Teulings et al. reported a high urine concentration of 3-OHAA in patients with untreated kidney cancer. Similarly, elevated urinary levels of 3-oxyAA were found in patients with renal cell carcinoma (RCC), though changes in 3-oxyKYN were statistically insignificant. Contrary to previous studies, Sato et al. postulated that elevated urinary KYN concentration is a predictive marker of RCC malignancy. In another study, elevated serum KYN and 3-OHAA concentrations were found in a group of 24 patients treated with IFN-γ for metastatic carcinoma, with a concomitant decrease in KYNA levels. Moreover, Trott et al. reported an interesting correlation between IDO activity and carcinogenesis. In addition to stimulation of Trp degradation in RCC, they showed increased expression of IDO not only in human cancer cells but also in the RCC environment. KYN metabolites and IDO inhibitors alone did not affect RCC cell or murine renal cell adenocarcinoma cell survival or proliferation in vitro. However, IFN-α together with methyl-thiohydantoin-dl-Trp, an IDO inhibitor, decreased renal cancer cell growth, highlighting the role of IDO inhibitors as potential anticancer agents. In the analysis of 40 human clear cell RCC samples, higher IDO expression, AhR expression, KYN levels, and KYN/ Trp ratios were found. Moreover, serum KYN was significantly elevated in RCC patients, whereas the KYN/ Trp ratio was linked to clinical stage, tumor size, Fuhrman grade, lymph node involvement, and visceral metastases. More evidence about enzymatic dysregulation of the KYN pathway in RCC was provided by Hornigold et al.. In contrast to IDO upregulation, a decrease in quinolinic acid phosphoribosyltransferase (QPRT) and HAAO expression was detected. Although the expression of most final enzymes in the KYN pathway was decreased, that of nicotinamide phosphoribosyltransferase, a crucial enzyme in the NAD salvage pathway, was increased in RCC. This interesting observation again shows dysregulation of the KYN pathway in renal cancer cells and highlights possible targets in anticancer treatment.
As AhR overexpression in RCC cells has been reported, KYNA, an AhR agonist, seems to be involved in carcinogenesis regulation. A lower KYNA content in RCC tissue was found, which in part can be related to loss of filtration by cancer tissue. On the other hand, it was shown that expression of human organic anion transporters 1 and 3, responsible for KYNA uptake, is markedly decreased in RCC tissue. Importantly, Walczak et al. demonstrated antiproliferative and antimigraine effects of KYNA on RCC Caki-2 cells. KYNA is also reported to inhibit cancer cell signaling, including p38 mitogen-activated protein kinase involved in cell cycle regulation. Interestingly, KYNA may inhibit multidrug resistance-associated protein 4 and breast cancer resistance protein, transporters responsible for drug resistance, possibly enhancing responsiveness to anticancer drugs, as presented by Walczak et al..
Drugs affecting the kynurenine pathway in the kidney
Based on the available literature, the KYN pathway seems to be an important regulator of kidney function under normal conditions, as well as in renal diseases, and drugs influencing KYN degradation may be promising agents in kidney disorder treatment. Nonetheless, data about sub-stances affecting KYN metabolism in the kidney are very limited (Fig. 3).
As mentioned previously, 1-methyl-d-Trp, an IDO inhibitor, causes renal damage in animal models of IgA nephropathy and mesangioproliferative glomerulonephritis, probably due to immune dysregulation. In contrast, IDO inhibition and, as a result, a reduction in KYN formation were reported to prevent ischemia–reperfusion injury and kidney damage in mice. Unfortunately, these findings were discredited by Čepcová et al., who presented an IDO-independent nephroprotective effect of 1-methyl-d-Trp in an ischemia-reperfusion model. The beneficial mechanisms of 1-methyl-d-Trp may include decreased toll-like receptor 4 signaling, impaired transforming growth factor beta signaling and epithelial–mesenchymal transition, and inappropriate activation of tubular epithelial cells, dendritic cells, NK cells, and T cells. Interestingly, in a recently published study, the antifibrotic effect of 1-methyl-d-Trp and another IDO inhibitor, BMS-98620, was confirmed in murine kidney slices and mice with unilateral ureteral obstruction. Based on these reports, we may conclude that pharmacological modulation of IDO activity remains an interesting approach for preventing kidney damage, especially under conditions related to tissue fibrosis, such as CKD.
Another potentially interesting group of agents in kidney function regulation is KAT inhibitors. Edwards and Mather reported that diclofenac given subcutaneously significantly increased kidney KYN and KYNA levels in rats. KYN and KYNA accumulation was suggested to be caused by inhibition of renal elimination. However, another mechanism of action was reported by Zakrocka et al.. In rat kidney homogenates, in vitro diclofenac was found to inhibit KAT activity and KYNA production, similar to gemfibrozil in another study. Similarly, angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers (ARBs) were observed to modify kidney KYNA levels. ACE-I lowers the KYNA concentration in rat kidney homogenates in vitro without affecting KAT activity, and ARBs decrease KYNA production by KAT inhibition in rat kidneys in vitro. Unfortunately, although Chmiel-Perzyńska et al. showed that after 4 weeks of administration, losartan decreases brain KYNA concentration in a rat model of diabetes mellitus, data on the long-term effect of ARBs on kidney KYN pathway activity are lacking. In particular, the effect of ARBs on KYNA synthesis seems to be of great importance and can be in part related to their mechanism of nephroprotection. Interestingly, Cernaro et al. observed lower serum KYN levels in patients with diabetic nephropathy taking angiotensin-converting enzyme inhibitors or ARBs. Additionally, the relationship between KYN and albuminuria, proteinuria, and GFR diminished in patients taking these drugs, suggesting their beneficial role in kidney function preservation. The plasma KYN/Trp ratio is also reported to be significantly associated with albuminuria and ARB responsiveness in diabetic kidney disease patients.
The presented results indicate a great need for further studies analyzing agents that potentially affect the KYN pathway and can be used in both diagnostic and therapeutic procedures.
Conclusions
The KYN pathway is a promising target in kidney disease prevention and treatment. Although many questions remain to be answered, future studies should explicitly explain the role of the KYN pathway in the pathogenesis of renal disorders, especially CKD. Searching for novel agents modulating KYN pathway activity may contribute to the introduction of new drugs for kidney diseases and significantly improve patient prognosis.
In recent years, research into the use of stem cells and a Chinese herbal remedy for the treatment of kidney diseases has gained great attention. The main mechanism of the two therapies is to promote the repair of injured renal tissues and protect the remaining renal functions.
The Chinese herbal remedy,cistanche, has been used in traditional Chinese medicine to treat various chronic kidney diseases since ancient times. It is reported that cistanche has the potential to reduce inflammation, reduce kidney fibrosis, and promote the synthesis of extracellular matrix components. It has been revealed that these effects are due to its bioactive components, including many phenolic substances, triterpenoids, and coumarins.
Click On Cistanche Tubulosa For Kidney Disease
Ask for more:
david.deng@wecistanche.com WhatApp:86 13632399501
On the other hand, stem cell technology has caused a revolution in medical practice. Research has demonstrated that stem cells can differentiate into various types of renal cells and perform therapeutic activities, including protecting the remaining functional renal tissues, slowing down tissue fibrosis, and repairing damaged renal tissues.
Ultimately, the combination of traditional Chinese medicine with modern science could be the key to treating various kidney diseases. This strategy has gradually been accepted by the medical community and studies have already shown that the combined therapy of cistanche and stem cell treatment may considerably reduce the mortality rate of kidney diseases.
In conclusion, the use of cistanche and stem cell treatment in the treatment of kidney diseases shows great potential and requires further research. The combined therapy of the two treatments could provide an improved treatment option for those facing kidney diseases.
Author contributions
Conceptualization, IZ; performed the literature search and data analysis, IZ; drafted and critically revised the work, IZ, and WZ. All authors have read and agreed to the published version of the manuscript.
Declarations
Conflict of interest Nothing to disclose.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license.
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