Lipoxynoids in the kidney

There are a variety of non-prostaglandin pathways for conversion of arachidonic acid, including lipoxygenase enzymes and epoxygenase enzymes such as cytochrome P-450. In a manner similar to that in which the cyclooxygenase pathways lead to the prostanoid family, ‘lipoxynoids’ refers to the family of products arising from this alternative group of pathways.Leukotrienes (LT's) are members of the lipoxynoid family arising from the action of 5-lipoxygenase enzymes. In the canine kidney, injections of leukotrienes C₄, D₄ and E₄ into the renal artery produced weak vasodilation at doses of 3–30 ug. Responses to LTC₄ and LTD₄ were similar and greater than responses to LTE₄, and responses were not different in animals which had received ibuprofen to inhibit prostaglandin synthesis. In contrast, these leukotrienes were potent vasoconstrictors of the mesenteric vascular bed in these same animals at doses of 0.01–0.3 ug. The order of potency was LTD₄ LTC₄ LTE₄. Effects of these LT's were not changed in the presence of ibuprofen. Responses to LTC₄ and LTD₄, but not LTE₄ were diminished approximately 50% after administration of FPL-55712 (2 mg/kg). Neither LTB₄ nor 5-HETE produced any change in renal or mesenteric blood flow at doses up to 30 ug.However, indirect evidence has been obtained suggesting that an endogenous lipoxynoid pathway can be activated in the canine kidney which results in the formation of a vasoconstrictor product. Injections of 1–4 mg AA into the renal artery of water-replete dogs leads to vasodilation which can be blocked by inhibitors of cyclooxygenase enzymes. However, when dogs were water deprived for 16–20 hours before the experiment, biphasic changes in renal blood flow were found. Ibuprofen blocked the vasodilator phase of the response but neither ibuprofen or the thromboxane synthesis inhibitor OKY-1581 had any inhibitory effect on the constrictor phase. The constrictor phase was blocked only following administration of ETYA or BW-755C, suggesting that the metabolites responsible for the constriction were lipoxynoids. Since LT's produce renal vasodilation, it appears that the pathway involved is not the 5-lipoxygenase system. These data suggest that other lipoxynoid pathways (e.g. 12-lipoxygenase, 15-lipoxygenase or cytochrome p-450) may play a role in the renal response to water deprivation. At present, however, it may not be possible to distinguish between these possible pathways .     

Ectonucleotidases in the kidney

Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2 and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule. NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K _m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes’ varied distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology and pathophysiology.     

Purinoceptors in the kidney

The multiple roles of extracellular ATP and its metabolite adenosine include broad areas, such as regulating vascular tone and inducing inflammation. This review will discuss purinoceptor-induced effects on renal vascular resistance, highlighting the key experiments providing a significant contribution to our current understanding of autoregulatory mechanisms. Emphasis will be placed on the purinoceptor subtypes involved in autoregulatory control by ATP and adenosine. Additionally, the role of purinoceptors in hypertension-associated impairment of autoregulatory efficiency will be discussed.     

肾脏尿酸转运体的研究进展

尿酸是人体内嘌呤代谢的终产物。在肝脏合成后,正常情况下约70%的尿酸在肾脏分泌,而一小部分则被分泌到肠内。肾脏是血尿酸稳态调节的主要器官,其调控依赖于尿酸转运体的转运。尿酸代谢紊乱或转运异常将导致高尿酸血症、痛风、痛风性肾结石等疾病。本文对肾脏尿酸转运体的研究进展进行综述。     

Apicobasal polarity in the kidney

The apicobasal polarization of epithelia is critical for many aspects of kidney function. Over the last decade there have been major advances in our understanding of the mechanisms that underlie this polarity. Critical to this understanding has been the identification of protein complexes on the apical and basolateral sides of epithelial cells that act in a mutually antagonistic manner to define these domains. Concomitant with the creation of apical and basolateral domains is the formation of highly specialized cell-cell junctions including adherens junctions and tight junctions. Recent research points to variability in the polarity and junctional complexes amongst different species and between different cell types of the kidney. Defects in apicobasal polarity are prominent in several disorders including acute renal failure and polycystic kidney disease.     

Self-renewal in the fly kidney

Tissue stem cells are typically rare and located in niches that prescribe low rates of cell division and survival. In the latest issue of Cell Stem Cell, Singh et al. (2007) demonstrate that, in the adult fly, epithelial cells exist that are neither in niches nor in small numbers, divide at high rates, and are multipotent.     

Renin in the human kidney

Summary We have localized the enzyme renin (EC 3.4.99.19) in the normal adult human kidney by immunohistology. Serial paraffin sections of kidneys were incubated with renin antisera and then processed by the peroxidase-antiperoxidase method. Renin immunoreactivity was observed in the juxta-glomerular epithelioid granular cells (JEG-cells) in the wall of the afferent and rarely of the efferent vessel of the glomerulus. JEG-cells have long cytoplasmic processes penetrating between adjacent cells. This suggests a possible paracrine release of renin. Staining of various segments of the tubular system was shown to be artifactual. The kidney proteins recognized by our anti-human renin antisera had similar characteristics to renin when determined by a combination of gel-electrophoretic and immunologic techniques. Renin immunostaining in the juxtaglomerular apparatus of the human kidney is discrete and reflects the low amount of extractable renin.Dedicated to Prof. G. Töndury on the occasion of his 75th birthday     

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

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Deciphering the SUMO code in the kidney

SUMOylation of proteins is an important regulatory element in modulating protein function and has been implicated in the pathogenesis of numerous human diseases such as cancers, neurodegenerative diseases, brain injuries, diabetes, and familial dilated cardiomyopathy. Growing evidence has pointed to a significant role of SUMO in kidney diseases such as DN, RCC, nephritis, AKI, hypertonic stress and nephrolithiasis. Recently, emerging studies in podocytes demonstrated that SUMO might have a protective role against podocyte apoptosis. However, the SUMO code responsible for beneficial outcome in the kidney remains to be decrypted. Our recent experiments have revealed that the expression of both SUMO and SUMOylated proteins is appreciably elevated in hypoxia‐induced tubular epithelial cells (TECs) as well as in the unilateral ureteric obstruction (UUO) mouse model, suggesting a role of SUMO in TECs injury and renal fibrosis. In this review, we attempt to decipher the SUMO code in the development of kidney diseases by summarizing the defined function of SUMO and looking forward to the potential role of SUMO in kidney diseases, especially in the pathology of renal fibrosis and CKD, with the goal of developing strategies that maximize correct interpretation in clinical therapy and prognosis.     

Liposome-mediated gene therapy in the kidney

Gene therapy directed to the kidney has been attempted to improve renal disorders such as inherited kidney diseases and common renal diseases that cause interstitial fibrosis, tubular atrophy, and glomerulosclerosis. Viral and non-viral vectors have been tried and been modulated to obtain sufficient transgene expression. However, gene delivery to the kidney is usually difficult because of characteristics of renal cell biology. Among non-viral vectors, the liposome system is a promising procedure for kidney-targeted gene therapy. Using cationic liposome, tubular cells were effectively transduced by retrograde injection of liposome/cDNA complex. Although transgene expression was reportedly modest using cationic liposomes, this method improved renal disease models such as carbonic anhydrase II deficiency and unilateral ureteral obstruction. In contrast, HVJ-liposome system is an effective transfection method to glomerular cells using intra-renal arterial infusion and improved glomerular disease models such as glomerulonephritis and glomerulosclerosis. In addition, intra-renal pelvic injection of DNA by HVJ-liposome system showed transgene expression in interstitial fibroblasts. In kidney-targeted gene therapy, liposome-mediated gene transfer is an attractive method because of its simplicity and reduced toxicity. In spite of modest transgene expression, several renal disease models were successfully modulated by liposome system. Although one limitation of liposome-mediated gene delivery is the duration of transgene expression, the liposome/cDNA complex can be repeatedly administered due to the absence of an immune response.     

Conditional gene targeting in the kidney

Complete mapping of the genome in a number of organisms provides a challenge for experimental nephrologists to identify potential functions of a vast number of new genes in the kidney. Since knockout technologies have evolved in the early eighties the mouse has become a valuable model organism. Researchers can now artificially eliminate the expression of specific genes in a mammalian organism and examine the phenotype. New developments have emerged that allow investigators to knock out a gene specifically in the kidney. Several kidney-specific promoters provide valuable tools and bacterial artificial chromosome (BAC) based techniques like recombineering will enhance both number and accuracy of new mouse lines with spatially controlled gene expression. In addition to spatial control, tetracycline- or tamoxifen-inducible systems, provide the possibility of influencing the temporal expression pattern of a gene enabling researchers to dissect its functions in adult organisms. Knocking out a gene will continue to be the gold standard for defining the role of a specific gene whereas tissue-specific gene knockdown using RNA interference represents an alternative approach for generating lower-priced and fast loss of function models. In addition to reverse genetic approaches, forward genetic techniques like random mutagenesis in mice continue to evolve and will enhance our understanding of disease mechanisms in the kidney.