Kidney research (2020)

Kidney research has been one major focus of publications of recent articles published in Acta physiologica. A number of articles deal with the elucidation of kidney disease models1-12 and the role of oxygen regulation in the kidney.13-16 This contribution focusses on articles that deal with kidney disease models and in the second part on articles that are related to the topic hypoxia and oxygen regulation. In the following section, we focus on three articles that make use of the unilateral ureter obstruction model. The unilateral ureter obstruction (UUO) is one animal model for the analysis of post-renal failure that has been studied recently.1, 3, 12 The models of the (UUO) have a clinical correlate, the hydronephrosis that can occur even prenatally.17 In a work by Wang et al the role of the matrix metalloproteinase-9 (MMP9) and neutrophils was analysed in this disease model.1 The enzyme MMP9 is thought to be important in the process of neutrophil invasion in the kidney. The authors investigated the mechanism of kidney injury on seven consecutive days after the obstruction surgery. The quantification of neutrophil infiltration was performed on Ly6G-stained cells of kidney lysates by means of a FACS assay. To test whether or not the neutrophils play a role in the development of kidney fibrosis in this model the authors used neutrophil depletion by means of Ly6G antibody injection. Interestingly, interstitial collagen deposition was lower in the neutrophil-depleted mice as compared to the isotype-antibody treated obstructed mice.1 The authors found by immunohistochemical staining that neutrophils are an important source for MMP9 in the obstructed kidney. To study the functional role of the MMP9 in this model the authors applied a MMP9 inhibitor that suppressed the infiltration of neutrophils and reduced the renal fibrosis. The authors conclude that a neutrophil depletion or MMP9 inhibition in an early stage of this acute kidney injury can relive the progression of the kidney fibrosis.1 The effectiveness of butaprost that is regarded to be a selective prostaglandin E2 EP2 receptor agonist18 was evaluated in the UUO mice model, in cell culture of Madin-Darby Canine Kidney (MDCK) cells and on human kidney slices in a work by Jensen et al3 The authors find that a treatment of 4 mg/kg/d butaprost attenuated the development of fibrosis in mice that underwent UUO surgery as seen by a reduction in the mRNA and protein expression of α-smooth muscle actin, fibronectin and collagen 1A1.3 In a kind of human model, the authors investigated the effectiveness of butaprost on human kidney slices that were exposed to TGF-β 48 hours where similar antifibrotic effects were observed. The kidney slices were obtained from functional healthy renal cortical tissue from patients undergoing tumour nephrectomies. The findings of the Jensen et al may stimulate further basic and clinical research in the fight against renal fibrosis. Genetic approaches where one specific gene is deleted or overexpressed are frequently used to study the function of that specific gene in an organism. This genetic approach was taken in a recent work published in Acta Physiologica by the researches Perretta-Tejedor et al12 who studied the role of the Cardiotrophin-1 in the murine UU0 fibrosis model where parts of the coding region of the exon one to three of Cardiotrophin-1 gene in the mouse was deleted19 (Cardiotrophin-1 -/- knock). Cardiotropin-1 is a member of the interleukin-6 family. They find that Cardiotrophin-1 deficiency increases tubulointerstitial fibrosis, parenchymal damage, apoptosis and renal inflammation12 in the UUO model. To reverse the experiment, the authors have supplemented exogenous Cardiotrophin-1 to the Cardiotrophin-1 knockout mice. Interestingly, the increased fibrosis as seen in the knockout resulting from the UUO was prevented and this treatment further ameliorates the UUO-induced renal fibrosis in the wild-type mice. The results of Perretta-Tejedor et al make Cardiotrophin-1 an interesting candidate for the treatment of renal fibrosis. A pharmacological study addresses the potential reno-protective effect of Tauroursodeoxycholic acid (TUDCA) that is a chemical chaperone and bile salt. The study was done in a rat model of ETB receptor deficiency with chronic high-salt-induced renal injury and inflammation.20 The authors studied the effect of TUDCA on histological and excretion markers and find that TUDCA treatment reduced the high-salt-induced renal damage which puts the substance on a candidate list for potential preventive use against chronic high-salt-induced renal damage. The development of nephrogenic diabetes insipidus may limit the therapeutic use of lithium in bipolar disorders.5 Previous pharmacological studies suggested a preventive effect of a blockade of P2Y12 receptor in this context. In ordered to gain further evidence about this the authors studied mice genetically lacking P2Y12-Receptor. The mice knocked out for this receptor showed less marked reduction in Aquaporine-2 that is instrumental in the reabsorption of water in the collecting duct as compared to the control animals under the LiCl-supplemented diet. This goes in line in the higher water intake and urine output of the wild-type under LiCl supplementation which again is less pronounced in the receptor knock-out animals. The authors suggest that drugs targeting the P2Y12 receptor might be a novel and save tool to treat nephrogenic diabetes insipidus.5 Death rates owing to sepsis are markedly higher in dialysis patients compared with the general population.21 During sepsis, one may find in patients alterations in the parathyroid hormone (PTH) and/or vitamin D signalling.8 In a work by Meuerer et al the effect of Lipopolysaccharides on Calcium and Pi transport was investigated. Lipopolysaccharides (LPS) are parts of the membrane of Gram-negative bacteria and can act as an antigen. The toll-like receptor 4 can recognize LPS. To investigate the action of LPS and the impact on Calcium transporters in the kidney the authors treated the mice with LPS. They observed a lipopolysaccharide-induced hypocalcaemia and hyperphosphataemia together with a decrease in glomerular filtration rate and urinary excretion of Ca2+ and Pi. Under LPS treatment the PTH levels were increased. Several transporters such as TRPV6, Calbindin-D9K, NCX1, PMCA1b and NaPi-2b were analysed with respect to their mRNA levels in the small and large intestine and NaPi-2a, NaPi-2c, PiT1 and PiT2 mRNA in the kidney. The authors find a number of changes in the transporter patterns, for example a LPS dose-dependent decrease in the TRPV6 mRNA. The TRPV6 protein is a membrane protein the is important in the resorption of Ca2+. In cell culture experiments, however, the authors find that a stimulation with LPS leads to an increase in TRPV6. This discrepancy might be explained by changes in hormonal aspects such as insulin resistance and corticosterone release.8 The take home message from this study might be that that hormonal as well as inflammatory stimuli may influence the expression of Ca2+ transporting proteins, however many features of the exact signalling remain to be explored in the future. In the following part, the focus is set to articles that deal with the role of oxygen, hypoxia and ischaemia. The kidney plays an important role for the formation of erythropoietin that is controlled by signalling pathways where hypoxia is the input. In addition, related mechanisms are involved in the development of kidney failure. This is why there is no surprise that the topic hypoxia and the role of oxygen regulation in the kidney is in the research interest of the researchers that have contributed to Acta Physiologica and literature review with the focus on the role of hypoxia in conjunction with kidney disease was compiled by Ow et al16 recently. Furosemide is a clinically widely used loop diuretic that targets the NKCC2 transporter22 in the thick ascending limb in the loop of Henle. In an interesting study Haddock et al investigate the renal response to furosemide by means of Magnetic Resonance Imaging (MRI) before and during furosemide.14 Renal arterial flow, oxygenation and perfusion was measured in nine humans. Isometric exercises served as a control for changes in renal haemodynamics. Furosemide induced an increase in renal medullary oxygenation, attributable exclusively to a decrease in renal oxygen consumption, since no change of renal arterial flow, cortical or medullary perfusion could be measured.14 This finding contributes to the understanding of the clinical effect of furosemide and its potential protective effect. Renal ischaemia and hypoxia may lead to an acute renal failure in humans. The involved cellular responses because of ischaemia are pivotal in the development of the renal failure. Eicosanoid formation is one aspect of these responses. Hoff et al investigated in an acute renal ischaemic rat model the action of a synthetic epoxyeicosatrienoic acid (EET) analogue. The authors find that after 45-minute clamping of the blood supply the levels of 20-HETE were increased about eightfold in a rat model. The effectiveness of the clamping was monitored by intraoperative magnet resonance imaging (MRI). In contrast, the free EETs were not accumulated. Interestingly, the authors analysed patient samples and those who developed a postoperative acute kidney failure showed increased preoperative increased 20-HETE and 8,9-EET levels. The authors hypothesized that an imbalance of 20-HETE and EETs can be counteracted by an intrarenal administration of synthetic 14,15-EET analogue. The effect of this pharmacological intervention was monitored by MR imaging and a signal pathway analysis of PI3kinases and mTORC2 was performed. The authors determined a number of changes in the signalling cascades and found that the EET analogue alleviated the ischaemia-related drop in creatinine clearance. Two main conclusions are drawn from this study, one that individual differences in the eicosanoid formation might be important for the risk of developing an acute kidney injury and two that the eicosanoid pathway might be a promising target for pharmacological interventions with respect to AKI prevention.2 Diabetes mellitus is the leading factor for the development of a chronic kidney disease. In the early stages in the development of a diabetic kidney disease one can observe glomerular hyperfiltration,23 increased oxygen consumption and tissue hypoxia and the activity of the renin-angiotensin-aldosterone system (RAAS) has been implicated in most of these early alterations.15 To investigate the RAAS peptide angiotensin (1-7) in this context renal haemodynamics and oxygen homeostasis were measured three weeks after administration of streptozotocin that induced an insulin requiring diabetes before and after acute intrarenal infusion of angiotensin (1-7) in a rat model. The authors find that diabetes results in increased sensitivity to elevated levels of angiotensin (1-7) which is manifested as inhibition of tubular sodium transport and normalization of glomerular filtration. In addition, elevated angiotensin (1-7) levels increase kidney oxygen consumption in the diabetic kidney further which affects tubular electrolyte transport efficiency negatively.15 The kidney is a complex organ and its untreated failure is life threatening. The reviewed articles deal with kidney (patho-)physiology in the context of mechanical, genetical and pharmacological interventions to shed light on basic mechanisms to understand the various disease processes in the kidney. However, many aspects of the pathophysiology of chronic kidney failure are still unknown and chronic kidney disease is regarded as a global public health problem.21 Chronic kidney disease is a major burden to the individual patient and kidney diseases drive substantially health care cost. In a recent work by Nichols et al it is stated: ‘Poorer kidney function and the presence of diabetes mellitus, cardiovascular disease, or heart failure drive substantial health care costs and increase the proportion of costs attributable to inpatient care. The large contribution of inpatient costs begins in earlier stages of CKD [Chronic kidney disease] and escalates as kidney function declines. Additional therapies to reduce CKD incidence, slow CKD progression and lower hospitalization risk are needed to benefit patients and reduce CKD's economic burden’.24 Those new therapeutic approaches require a better understanding of the underlying mechanisms. Basic kidney research will be an essential contribution in that regard. None.