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

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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.     

Aldosterone and the kidney

The mineralocorticoid aldosterone is a key regulator of blood pressure, fluid and electrolyte homeostasis, and acts via the mineralocorticoid receptor (MR). In recent years, an increasing number of studies revealed deleterious effects of aldosterone via its receptor. Especially in patients with primary hyperaldosteronism (PHA) a significant higher risk of developing cardiovascular comorbidities and comortalities was reported. Also renal insufficiency is clearly increased in patients with PHA indicating a role of aldosterone and the MR in the pathogenesis of renal injury. It has been shown that aldosterone in combination with an elevated salt intake, leads to renal inflammation, fibrosis, podocyte injury, and mesangial cell proliferation. This review focuses on the current knowledge of aldosterone effects in the kidney and highlights this topic from 2 perspectives: from clinical medicine and from experimental studies.     

Antibody formation in experimental kidney failure and in the early stages of restorative kidney growth in mice

The ability of spleen cells to respond with antibody formation to a foreign antigen (sheep erythrocytes) was studied in mice at different kidney lesions (uni- and bilateral nephrectomy, ureter ligation, pseudo-operation, wound of one kidney) during the early postoperation period (1-72 h). In the case of bilateral nephrectomy, the reliable increase in the number of antibody-forming cells (AFC) was noted already within 1 h after the operation, in the case of unilateral nephrectomy within 12 h. In the case of bi- and unilateral ligations of ureter, the response was delayed by 3 and 5 h, respectively. Sham operation and kidney wound did not stimulate antibody formation. It is suggested that the antibody-forming ability of the spleen cells does not depend on stress, renal deficiency or destructive changes and that the antibody formation is activated by disturbances in the ratio of immunoregulatory cells.     

Selenium and selenoproteins in the rat kidney

Kidney tissue contains a high concentration of selenium that is not accounted for by the known selenoprotein glutathione peroxidase (glutathione: hydrogen-peroxide oxidoreductase, EC 1.11.1.9). In order to investigate the nonglutathione peroxidase selenium, rats were isotopically labeled with [75Se]selenite over a 10-day period. After this time half of the 75Se in kidney homogenate was found in the particulate subcellular fractions. The kidney lysosomes contained unusually high levels of 75Se, yet they did not contain correspondingly high levels of glutathione peroxidase activity. Two selenoproteins having molecular weights less than 40 000 were resolved by gel filtration from a kidney supernatant fraction. A third selenoprotein exhibited a molecular weight of 75 000. This protein contained one 75 000 molecular-weight subunit, and its selenium was in the amino acid selenocysteine. The 75 000 molecular-weight protein was chromatographically distinct from glutathione peroxidase. In order to determine if these selenoproteins protect against cadmium toxicity, 109CdCl2 was administered to rats that were isotopically prelabeled with 75Se. At 3, 25 and 72 h after 109Cd administration, no 109Cd was associated with selenium-containing proteins. Two of the nonglutathione peroxidase selenoproteins were apparently unique to the kidney.     

Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease

Primary cilia project from the surface of most vertebrate cells and are thought to be sensory organelles. Defects in primary cilia lead to cystic kidney disease, although the ciliary mechanisms that promote and maintain normal renal function remain incompletely understood. In this work, we generated a floxed allele of the ciliary assembly gene Ift20. Deleting this gene specifically in kidney collecting duct cells prevents cilia formation and promotes rapid postnatal cystic expansion of the kidney. Dividing collecting duct cells in early stages of cyst formation fail to properly orient their mitotic spindles along the tubule, whereas nondividing cells improperly position their centrosomes. At later stages, cells lacking cilia have increased canonical Wnt signaling and increased rates of proliferation. Thus, IFT20 functions to couple extracellular events to cell proliferation and differentiation.