Experimental Models Of Kidney Disease Research Articles

#1290 Adverse proinflammatory responses in the kidney after FGF23 administration in three murine kidney disease models

Abstract Background and Aims The hormone FGF23 is a biomarker associated with morbidity and mortality in individuals with and without kidney disease, but the role of FGF23 excess as a pathogenic factor is incompletely understood. Here, we investigated renal FGF23 signaling in kidney disease models. Method This study used three independent disease models: i) Male C57BL/6 mice (n = 16) were treated with Freud's adjuvant and nephrotoxic serum (NTS) to induce anti-glomerular basement membrane (anti-GBM) disease. ii) Female BALB/c mice (n = 8) were treated with adriamycin (doxorubicin) 10.5 mg/kg to induce focal and segmental glomerulosclerosis (FSGS). iii) Male DBA/2J mice (n = 20) were fed a diet containing adenine 0.2%. Control mice of the respective same strain and sex received vehicle injections. Mice of the anti-GBM and FSGS models and controls received intravenous injections of recombinant FGF23 1 µg or vehicle for six consecutive days (anti-GBM) or once (FSGS), with dissection 24 h after the last injection. Mice of the adenine model were dissected after 15 weeks. Following dissection, ex vivo precision-cut kidney slices (PCKS) were obtained from n = 4 mice and maintained for 24 at 37°C, 95% O2 and 5% CO2, followed by a 1 h treatment with recombinant FGF23 200 ng/ml or vehicle. Glomerular filtration rate (GFR) or renal retention parameters in serum and albuminuria were assessed. Kidneys underwent histological assessment using hematoxylin & eosin or Masson's trichrome. Renal RNA was isolated for bulk RNAseq. Differential gene expression was assessed to determine the effect of FGF23 treatment in disease-free controls, in each disease model, and the interaction between FGF23 X disease effect for the anti-GBM and FSGS groups. Gene set enrichment analysis was performed with a focus on the immune system. Results Anti-GBM mice showed a 45 ± 27% GFR decline (mean ± SD) compared to baseline, whereas controls showed an GFR increase of 11 ± 36% (p < 0.01). Kidney histology revealed an interstitial infiltrate. The FSGS model showed elevated serum creatinine and albuminuria, and hypercellularity in some glomeruli. Mice of the adenine model showed progressively increased blood urea nitrogen concentrations starting after 2 weeks, up to a 3-fold increase at week 14. Histology revealed interstitial fibrosis and tubular atrophy. Bulk RNAseq revealed proinflammatory transcriptional signatures after FGF23 treatment in all disease models, regardless of which timepoint or model: In the anti-GBM model, Hallmark gene sets of inflammatory response, interferon-α response, interferon-β response and allograft rejection were significantly increased after 6 days of FGF23 treatment, whereas disease-free controls showed no significantly changed immune gene sets after 6 days of FGF23. In FSGS mice, none of the Hallmark gene sets were changed after 1 FGF23 injection, but top individual gene expression affected by 1 FGF23 injection were an increased proinflammatory transcription factor Cebpb and an increased DNA damage transcript Dclre1b. Finally, the PCKS of adenine model revealed no significant Hallmark gene sets, but the two genes with differential expression were a proinflammatory macrophage/fibroblast chemokine Ccl4 (increased) and an immunoglobulin heavy variable Ighv2-2 (decreased). Conclusion FGF23-driven patterns of proinflammatory gene expression were observed in three experimental models of kidney disease, both in vivo and ex vivo assessment of FGF23 signaling, thus excluding effects of FGF23 on other organs. As these findings were limited to transcriptional analyses, the present data warrant further confirmation and exploration of FGF23 as a pathogenic agent in kidney disease.

Three-dimensional morphometry of kidney in New Zealand rabbit using unbiased design-based stereology.

The rabbit is widely used as a laboratory animal in experimental models of kidney diseases. This species is also important from a veterinary perspective as a companion animal. Stereology has been accepted as an accurate approach to kidney morphometry. The objective of the present project was to provide normal quantitative stereological parameters for adult rabbit kidneys. The left kidneys of five adult male New Zealand rabbits were used. Isotropic sections were obtained using the orientation method. Total kidney volume was calculated by the Cavalieri principle. The volume fraction of the renal structures was estimated using the point counting system. The lengths of the proximal convoluted tubule (PCT) and distal convoluted tubule (DCT) were calculated using counting frames. The total glomerular number was accounted for using the physical/fractionator technique. The mean glomerular volume was obtained by dividing the total volume of glomeruli by their total number. The total volume of rabbit kidneys calculated was 10.39 ± 1.98 cm3. The fractional volume of the kidney cortex and medulla accounted for 57.79 ± 0.65% and 42.2 ± 0.65%, respectively. The total glomerular volume was 2.18 ± 0.32% of the whole kidney. The total number of glomeruli in the rabbit kidney was estimated as 204.68 ± 12 × 103. The mean glomerular volume measured 1.07 ± 0.12 × 106 μm3. The total length of PCT and DCT was 2.96 ± 0.29 km and 1.38 ± 0.24 km, respectively. These findings can be used as a reference in experimental nephrology research and may help to expand the knowledge of nephrology in mammals by comparing with available data on humans and other species. RESEARCH HIGHLIGHTS: Three-dimensional morphometry of adult rabbit kidney structures was analyzed using quantitative stereology. Total volume of kidney, fractional volume of cortex and medulla, length of renal tubules and number of nephrons were estimated. These three-dimensional morphometrical data can be used as a reference in experimental nephrology research and may help to expand the knowledge of nephrology in mammals.

Експериментальна патологія нирок: моделі токсичних нефропатій

When conducting experimental studies, the question of an adequate model of renal pathology is problematic, therefore, the range of choice of methods of reproduction is extremely wide. The paper highlights the main modern methods of modeling and the principles of choosing a model of nephropathy for the study of changes in kidney functions and processes. It also investigates the effectiveness of pharmacological correction under the conditions of exposure to exotoxins. Attention is focused on models with predominant damage to nephron sections with established pathogenetic features of the course of acute and chronic toxic nephropathy. Aim of research is elucidation of methods of modeling toxic nephropathies, using the results of our research laboratories and modern data from the literature on experimental nephrology. Materials and Methods. Analytical methods are used in the work: collection of scientific information on the problem, data analysis and scientific generalization of results. Results and Conclusions. Experimental models of kidney diseases are diverse, which allows to carefully study the pathogenesis of renal pathology and to develop effective therapeutic strategies. At the same time, in experimental studies, in a number of cases, it is necessary to simulate kidney disease with differentiated damage to the glomerular or tubular part of the nephron. The development of effective medical interventions to reduce exotoxin-induced nephrotoxicity largely depends on the chosen experimental model, respectively, on the understanding of the pathophysiology of toxic nephropathies. Keywords: experimental nephrology, differentiated damage of the nephron, toxic nephropathies.

Ferroptosis is involved in passive Heymann nephritis in rats

Ferroptosis is found to be involved in some experimental models of kidney diseases, but its role in membrane nephropathy (MN) is still unclear. The purpose of this study is to explore whether ferroptosis occurred in MN, and the role of ferritinophagy. In this study, passive Heymann nephritis (PHN) rats were induced by single tail vein injection of anti-Fx1A serum, and normal rats were used as control. The changes of 24 h urinary protein, serum biochemical parameters, renal pathological damage, iron content, lipid peroxidation parameters, ferroptosis markers, and ferritinophagy markers were evaluated in the two groups. Compared with the control group, PHN rats showed obvious proteinuria, hypoproteinemia, and hyperlipidemia. Besides, more severe renal pathological damage and higher Fe2+ levels were observed in PHN rats, and the levels of malondialdehyde (MDA) increased significantly, while the levels of superoxide Dismutase (SOD) and glutathione (GSH) decreased. In addition, the expression of glutathione peroxidase 4 (GPX4) in renal tissues of PHN rats decreased significantly, while the expression of transferrin receptor (TFR) and acyl-CoA synthetase long-chain family member 4 (ACSL4) increased. The expression of microtubule associated protein 1 light chain 3 (LC3) II/LC3I and nuclear receptor coactivator 4 (NCOA4) increased significantly. Therefore, our study shows that ferroptosis is involved in the pathological damage of MN, and companied by activation of ferritinophagy.

Macrophage Function Modulated by tPA Signaling in Mouse Experimental Kidney Disease Models.

Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular signal pathways, modulating macrophage function in response to kidney injury. In this review, we discuss the current understanding of tPA-modulated macrophage function and underlying signaling mechanisms during kidney fibrosis and inflammation.

The impact of hypoxia-inducible factors in the pathogenesis of kidney diseases: a link through cell metabolism.

Kidneys are sensitive to disturbances in oxygen homeostasis. Hypoxia and activation of the hypoxia-inducible factor (HIF) pathway alter the expression of genes involved in the metabolism of renal and immune cells, interfering with their functioning. Whether the transcriptional activity of HIF protects the kidneys or participates in the pathogenesis of renal diseases is unclear. Several studies have indicated that HIF signaling promotes fibrosis in experimental models of kidney disease. Other reports showed a protective effect of HIF activation on kidney inflammation and injury. In addition to the direct effect of HIF on the kidneys, experimental evidence indicates that HIF-mediated metabolic shift activates inflammatory cells, supporting the HIF cascade as a link between lung or gut damage and worsening of renal disease. Although hypoxia and HIF activation are present in several scenarios of renal diseases, further investigations are needed to clarify whether interfering with the HIF pathway is beneficial in different pathological contexts.

Editorial introductions.

Current Opinion in Nephrology and Hypertension was launched in 1992. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of nephrology and hypertension is divided into 12 sections that are each reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Agnes B FogoAgnes B FogoProfessor Agnes Borge Fogo completed her medical training at Vanderbilt University Medical School, USA. She has remained at Vanderbilt for residency in pathology and fellowship in renal pathology and experimental kidney disease models. Her main research interests are focused on potential regression of chronic kidney disease and tubular-glomerular crosstalk in this process, pursued with funding from the National Institutes of Health and other sources. She is also dedicated to diagnostic renal pathology and has created an online Atlas of Renal Pathology with the American Journal of Kidney Disease and the National Kidney Foundation. She has also authored two books on renal pathology. Prof. Fogo enjoys teaching renal pathology and received the Robert G. Narins award from the American Society of Nephrology in 2011 as well as the Roscoe R. Robinson award from the International Society of Nephrology in 2019, for her contributions in teaching. She is currently President of the ISN and the John L. Shapiro Professor of Pathology, Microbiology and Immunology, Professor of Medicine and Paediatrics and Director of the Renal/Electron Microscopy Laboratory at Vanderbilt University Medical Center, Nashville, Tennessee, USA. Navdeep TangriNavdeep TangriDr Tangri is an attending physician and Professor in the Division of Nephrology, Department of Internal Medicine, and the Rady Faculty of Community Health Sciences at the University of Manitoba, Winnipeg, Canada. Dr Tangri's research program is clinical, translational, and focused on improving clinical decision making for patients with advanced chronic kidney disease. He developed and validated the Kidney Failure Risk Equation to predict the need for dialysis in patients with CKD and is presently engaged in multiple validation and implementation exercises to increase the uptake of the KFRE. In addition, Dr Tangri is conducting a large prospective study on frailty, physical and cognitive function in advanced CKD, as well as leading a multinational randomized trial on the safety and efficacy of a new therapy in this population. He has published over 300 manuscripts, presented at multiple national and international scientific meetings, and is a recipient of the CIHR New Investigator Award and a CIHR Foundation grant.

Redox Signaling in Chronic Kidney Disease-Associated Cachexia.

Redox signaling alterations contribute to chronic kidney disease (CKD)-associated cachexia. This review aims to summarize studies about redox pathophysiology in CKD-associated cachexia and muscle wasting and to discuss potential therapeutic approaches based on antioxidant and anti-inflammatory molecules to restore redox homeostasis. Enzymatic and non-enzymatic systems of antioxidant molecules have been studied in experimental models of kidney diseases and patients with CKD. Oxidative stress is increased by several factors present in CKD, including uremic toxins, inflammation, and metabolic and hormone alterations, leading to muscle wasting. Rehabilitative nutritional and physical exercises have shown beneficial effects for CKD-associated cachexia. Anti-inflammatory molecules have also been tested in experimental models of CKD. The importance of oxidative stress has been shown by experimental studies in which antioxidant therapies ameliorated CKD and its associated complications in the 5/6 nephrectomy model. Treatment of CKD-associated cachexia is a challenge and further studies are necessary to investigate potential therapies involving antioxidant therapy.

Periostin as a Biomarker in the Setting of Glomerular Diseases-A Review of the Current Literature.

Chronic kidney disease (CKD) is a highly prevalent and potential progressive condition with life-threatening consequences. Glomerular diseases (glomerulopathies) are causes of CKD that are potentially amenable by specific therapies. Significant resources have been invested in the identification of novel biomarkers of CKD progression and new targets for treatment. By using experimental models of kidney diseases, periostin has been identified amongst the most represented matricellular proteins that are commonly involved in the inflammation and fibrosis that characterize progressive kidney diseases. Periostin is highly expressed during organogenesis, with scarce expression in mature healthy tissues, but it is upregulated in multiple disease settings characterized by tissue injury and remodeling. Periostin was the most highly expressed matriceal protein in both animal models and in patients with glomerulopathies. Given that periostin is readily secreted from injury sites, and the variations in its humoral levels compared to the normal state were easily detectable, its potential role as a biomarker is suggested. Moreover, periostin expression was correlated with the degree of histological damage and with kidney function decline in patients with CKD secondary to both inflammatory (IgA nephropathy) and non-inflammatory (membranous nephropathy) glomerulopathies, while also displaying variability secondary to treatment response. The scope of this review is to summarize the existing evidence that supports the role of periostin as a novel biomarker in glomerulopathies.

The Effect of Polyphenols on Kidney Disease: Targeting Mitochondria

Mitochondrial function, including oxidative phosphorylation (OXPHOS), mitochondrial biogenesis, and mitochondria dynamics, are essential for the maintenance of renal health. Through modulation of mitochondrial function, the kidneys are able to sustain or recover acute kidney injury (AKI), chronic kidney disease (CKD), nephrotoxicity, nephropathy, and ischemia perfusion. Therapeutic improvement in mitochondrial function in the kidneys is related to the regulation of adenosine triphosphate (ATP) production, free radicals scavenging, decline in apoptosis, and inflammation. Dietary antioxidants, notably polyphenols present in fruits, vegetables, and plants, have attracted attention as effective dietary and pharmacological interventions. Considerable evidence shows that polyphenols protect against mitochondrial damage in different experimental models of kidney disease. Mechanistically, polyphenols regulate the mitochondrial redox status, apoptosis, and multiple intercellular signaling pathways. Therefore, this review attempts to focus on the role of polyphenols in the prevention or treatment of kidney disease and explore the molecular mechanisms associated with their pharmacological activity.

Editorial introductions.

Current Opinion in Nephrology and Hypertension was launched in 1992. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of nephrology and hypertension is divided into 12 sections that are each reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Agnes B. FogoAgnes B. FogoProfessor Agnes B. Fogo completed her medical training at Vanderbilt University Medical School, USA. She has remained at Vanderbilt for residency in pathology and fellowship in renal pathology and experimental kidney disease models. Her main research interests are focused on potential regression of chronic kidney disease and tubular-glomerular crosstalk in this process, pursued with funding from the National Institutes of Health and other sources. She is also dedicated to diagnostic renal pathology and has created an online Atlas of Renal Pathology with the American Journal of Kidney Disease and the National Kidney Foundation. She has also authored two books on renal pathology. Prof. Fogo enjoys teaching renal pathology and received the Robert G. Narins award from the American Society of Nephrology in 2011 as well as the Roscoe R. Robinson award from the International Society of Nephrology in 2019, for her contributions in teaching. She is currently President of the ISN and the John L. Shapiro Professor of Pathology, Microbiology and Immunology, Professor of Medicine and Paediatrics and Director of the Renal/Electron Microscopy Laboratory at Vanderbilt University Medical Center, Nashville, Tennessee, USA. Navdeep TangriNavdeep TangriDr Tangri is an attending physician and Associate Professor in the Division of Nephrology, Department of Medicine and the Department of Community Health Sciences at the University of Manitoba, Canada. Dr Tangri's research program is clinical and translational and focused on improving clinical decision making for patients with advanced chronic kidney disease. He developed and validated the Kidney Failure Risk Equation (KFRE) to predict the need for dialysis in patients with Chronic Kidney Disease (CKD), and is presently engaged in multiple validation and implementation exercises to increase the uptake of the KFRE. In addition, Dr Tangri is conducting a large prospective study on frailty, physical and cognitive function in advanced CKD, as well as leading a multinational randomized trial on the safety and efficacy of a new therapy in this population. He has published over 250 manuscripts and presented at multiple national and international scientific meetings. He is also a recipient of the CIHR New Investigator Award and a CIHR Foundation grant.

Editorial introductions.

Current Opinion in Nephrology and Hypertension was launched in 1992. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of nephrology and hypertension is divided into 12 sections that are each reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Agnes B. FogoAgnes B. FogoProfessor Agnes Borge Fogo completed her medical training at Vanderbilt University Medical School, USA. She has remained at Vanderbilt for residency in pathology and fellowship in renal pathology and experimental kidney disease models. Her main research interests are focused on potential regression of chronic kidney disease and tubular-glomerular crosstalk in this process, pursued with funding from the National Institutes of Health and other sources. She is also dedicated to diagnostic renal pathology and has created an online Atlas of Renal Pathology with the American Journal of Kidney Disease and the National Kidney Foundation. She has also authored two books on renal pathology. Prof. Fogo enjoys teaching renal pathology and received the Robert G. Narins award from the American Society of Nephrology in 2011, as well as the Roscoe R. Robinson award from the International Society of Nephrology in 2019, for her contributions in teaching. She is currently President of the ISN and the John L. Shapiro Professor of Pathology, Microbiology and Immunology, Professor of Medicine and Paediatrics and Director of the Renal/Electron Microscopy Laboratory at Vanderbilt University Medical Center, Nashville, Tennessee, USA. Navdeep TangriNavdeep TangriDr Tangri is an attending physician and Associate Professor in the Division of Nephrology, Department of Medicine and the Department of Community Health Sciences at the University of Manitoba, Canada. Dr Tangri's research program is clinical and translational and focused on improving clinical decision making for patients with advanced chronic kidney disease. He developed and validated the Kidney Failure Risk Equation (KFRE) to predict the need for dialysis in patients with Chronic Kidney Disease (CKD) and is presently engaged in multiple validation and implementation exercises to increase the uptake of the KFRE. In addition, Dr Tangri is conducting a large prospective study on frailty, physical and cognitive function in advanced CKD, as well as leading a multinational randomized trial on the safety and efficacy of a new therapy in this population. He has published over 250 manuscripts and presented at multiple national and international scientific meetings. He is also a recipient of the CIHR New Investigator Award and a CIHR Foundation grant.

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches.

Mitochondria are energy-producing organelles that not only satisfy the high metabolic demands of the kidney but sense and respond to kidney injury-induced oxidative stress and inflammation. Kidneys are rich in mitochondria. Mitochondrial dysfunction plays a critical role in the progression of acute kidney injury and chronic kidney disease. Mitochondrial responses to specific stimuli are highly regulated and synergistically modulated by tightly interconnected processes, including mitochondrial dynamics (fission, fusion) and mitophagy. The counterbalance between these processes is essential in maintaining a healthy network of mitochondria. Recent literature suggests that alterations in mitochondrial dynamics are implicated in kidney injury and the progression of kidney diseases. A decrease in mitochondrial fusion promotes fission-induced mitochondrial fragmentation, but a reduction in mitochondrial fission produces excessive mitochondrial elongation. The removal of dysfunctional mitochondria by mitophagy is crucial for their quality control. Defective mitochondrial function disrupts cellular redox potential and can cause cell death. Mitochondrial DNA derived from damaged cells also act as damage-associated molecular patterns to recruit immune cells and the inflammatory response can further exaggerate kidney injury. This review provides a comprehensive overview of the role of mitochondrial dysfunction in acute kidney injury and chronic kidney disease. We discuss the processes that control mitochondrial stress responses to kidney injury and review recent advances in understanding the role of mitochondrial dysfunction in inflammation and tissue damage through the use of different experimental models of kidney disease. We also describe potential mitochondria-targeted therapeutic approaches.

Prediction Value of Serum NGAL in the Diagnosis and Prognosis of Experimental Acute and Chronic Kidney Injuries.

Sensitive and accurate serum biomarkers for monitoring acute and chronic kidney disease progression are more convenient and can better evaluate drug efficiency in pharmacological research. Neutrophil Gelatinase-associated Lipocalin (NGAL) is considered a hopeful early biomarker of acute kidney injury (AKI), but its utility in early prediction and prognosis of diabetic nephropathy (DN) and immune-mediated glomerulonephritis is still not clear. Moreover, detailed prognosis studies of NGAL in AKI are lacking, and most studies use a urine source. In the current study, through two experimental AKI and two chronic kidney injury animal models, serum NGAL (sNGAL) prediction values on diagnosis and prognosis of kidney injuries in animal disease models have been investigated thoroughly. Four experimental kidney disease models include cisplatin-induced and lipopolysaccharide (LPS)-induced AKI, streptozocin-induced diabetic nephropathy (DN), and cationized-bovine serum albumin (c-BSA)-induced membranous nephropathy (MN), respectively. The sNGAL concentration was measured at different stages of kidney injury (KI) in each experimental model, and receiver operating characteristic (ROC) analyses were performed to investigate the diagnosis efficiency of sNGAL for KI. Western blot and immunohistochemistry were used to measure the protein levels in the kidneys, and pathological analysis was used as the gold standard to confirm KI. Results suggest that sNGAL can predict early diagnosis of cisplatin-induced AKI accurately but is less powerful in later stages compared to blood urea nitrogen (BUN) and serum creatinine (Scr). sNGAL is sensitive but lacks specificity to evaluate early kidney injury for LPS-induced AKI under low-dosage LPS challenge. sNGAL is not an efficient biomarker for early diagnosis of STZ-induced DN, but sNGAL is an efficient predictor for the early diagnosis and prognosis of immune-mediated MN. In conclusion, application of sNGAL as a kidney injury biomarker to determine the diagnosis and prognosis in pharmacological studies is dependent on experimental animal models.

The role of inflammasomes in kidney disease.

Inflammasomes are multiprotein innate immune complexes that regulate caspase-dependent inflammation and cell death. Pattern recognition receptors, such as nucleotide-binding oligomerization domain (NOD)-like receptors and absent in melanoma 2 (AIM2)-like receptors, sense danger signals or cellular events to activate canonical inflammasomes, resultingin caspase 1 activation, pyroptosis and the secretion of IL-1β and IL-18. Non-canonical inflammasomes can be activated by intracellular lipopolysaccharides, toxins and some cell signalling pathways. These inflammasomes regulate the activation of alternative caspases (caspase 4, caspase 5, caspase 11 and caspase 8) that lead to pyroptosis, apoptosis and the regulation of other cellular pathways. Many inflammasome-related genes and proteins have beenimplicated in animal models of kidney disease. In particular, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome has been shown to contribute to a wide range of acuteand chronic microbial and non-microbial kidney diseases via canonical and non-canonical mechanisms that regulate inflammation, pyroptosis, apoptosis and fibrosis. In patients with chronic kidney disease, immunomodulation therapies targeting IL-1β such as canakinumab have been shown to prevent cardiovascular events. Moreover, findings in experimental models of kidney disease suggest that small-molecule inhibitors targeting NLRP3 and other inflammasome components are promising therapeutic agents.

Experimental models of kidney diseases to study pathogenetic mechanisms and efficacy of pharmacological correction against the background of comorbid pathology

The aim of our study is to report about modern models of kidney diseases associated with other pathological conditions for experimental studies of pathogenic mechanisms and efficacy of pharmacological correction. The study deals with experimental models reasonably to be applied in investigation of comorbid pathology pathogenesis and efficacy of its pharmacological correction. The attention is focused on the models of cardio-renal, hepatic-renal syndromes and multiple organ hypoxic histochemical injury simulated in laboratory rats. These models are characterized by easy modeling, simulation of comorbidity pathogenesis, acute and chronic periods of diseases available, induced by the antibiotic Doxorubicin or exotoxins – corrosive sublimate, sodium nitrite, and 2,4-dinitrophenol. Conclusions. The models of cardio-renal, hepatic-renal syndromes and hypoxic histochemical injury of the body are found to be optimal to perform multipurpose studies of physiological, pathophysiological, pharmacological directions with maximal similarity of the results obtained to clinical-therapeutic peculiarities of comorbid pathology.

Therapeutic effects of histone deacetylase inhibitors on kidney disease.

Increasing evidence has shown the involvement of histone deacetylases (HDACs) in the development and progression of various renal diseases, highlighting its inhibition as a promising therapeutic strategy to prevent kidney diseases. Accordingly, numerous studies have shown that HDAC inhibitors protect the kidneys from various diseases through their effects on multiple pathways, such as suppression of transforming growth factor-β signaling pathway and nuclear factor-κB signaling pathways, augmentation of apoptosis, and inhibition of angiogenesis. To develop more effective and less toxic isoform-selective HDAC inhibitors and further improve clinical outcomes, it is necessary to identify and understand the mechanisms involved in the pathogenesis and progression of renal diseases. This review focuses on the roles of HDAC inhibitors and the mechanisms involved in their therapeutic effects in experimental models of kidney diseases including glomerulosclerosis, tubulointerstitial fibrosis, glomerular and tubulointerstitial inflammation, lupus nephritis, polycystic kidney disease, and renal cell carcinoma (RCC).

The smell of renal protection against chronic kidney disease: Hydrogen sulfide offers a potential stinky remedy.

Chronic kidney disease (CKD) is a common global health challenge characterized by irreversible pathological processes that reduce kidney function and culminates in development of end-stage renal disease. It is associated with increased morbidity and mortality in addition to increased caregiver burden and higher financial cost. A central player in CKD pathogenesis and progression is renal hypoxia. Renal hypoxia stimulates induction of oxidative and endoplasmic reticulum stress, inflammation and tubulointerstitial fibrosis, which in turn, promote cellular susceptibility and further aggravate hypoxia, thus forming a pathological vicious cycle in CKD progression. Although the importance of CKD is widely appreciated, including improvements in the quality of existing therapies such as dialysis and transplantation, new therapeutic options are limited, as there is still increased morbidity, mortality and poor quality of life among CKD patients. Growing evidence indicates that hydrogen sulfide (H2S), a small gaseous signaling molecule with an obnoxious smell, accumulates in the renal medulla under hypoxic conditions, and functions as an oxygen sensor that restores oxygen balance and increases medullary flow. Moreover, plasma H2S level has been recently reported to be markedly reduced in CKD patients and animal models. Also, H2S has been established to possess potent antioxidant, anti-inflammatory, and anti-fibrotic properties in several experimental models of kidney diseases, suggesting that its supplementation could protect against CKD and retard its progression. The purpose of this review is to discuss current clinical and experimental developments regarding CKD, its pathophysiology, and potential cellular and molecular mechanisms of protection by H2S in experimental models of CKD.

Adrenomedullin ameliorates podocyte injury induced by puromycin aminonucleoside in vitro and in vivo through modulation of Rho GTPases.

Podocyte injury is a key event in proteinuric kidney disease and eventually glomerular scarring. While adrenomedullin (AM), a potent vasodilatory peptide, has been reported to confer renoprotection in several experimental models of kidney diseases, its effect on injured podocytes and the related mechanism is still largely unknown. Employing Western blotting analysis, immunoprecipitation and immunofluorescence, we investigated the effects of AM on the expressions of podocyte cytoskeletal proteins and Rho-family small GTPases (Rho GTPases) in puromycin aminonucleoside (PAN)-induced podocyte injury, both in cultured podocytes and in PAN nephrosis rats. Urinary protein excretion and the morphologic changes of kidney in PAN nephrosis rats were evaluated. Glutathione-S-transferase pull-down assay was applied for Rho GTPases activity. PAN induced massive albuminuria and morphologic injury, which were significantly mitigated by AM administration. AM significantly antagonized not only the PAN-decreased expressions of synaptopodin, nephrin, CD2AP and podocin, but also the PAN-disrupted interactions between synaptopodin-RhoA, nephrin-CD2AP, and CD2AP-Rac1-cortactin. These effects of AM in cultured podocytes were mostly significantly blocked by H89, a PKA inhibitor. AM dramatically upregulated the PAN-induced Rho GTPases protein expressions and their activities. PAN increased the expressions of endogenous AM and its receptor RAMP2 which was furthermore upregulated by AM administration. AM alleviated podocyte injury induced by PAN both in cell culture and in PAN nephrosis. The beneficial effects of AM on podocytes can be attributable to direct modulation of podocyte cytoskeletal proteins and Rho GTPases, mainly via a PKA-dependent pathway.

Tamoxifen for induction of Cre-recombination may confound fibrosis studies in female mice.

A variety of conditional knock-out mice relying on Tamoxifen-driven ERT2/Cre -mediated recombination are available and have been used to study involvement of specific genes in kidney disease. However, recent data suggest that Tamoxifen itself might attenuate fibrosis when administered during experimental models of kidney disease. It has remained unclear whether this still applies also if kidney damage is initiated after a wash-out period has been implemented. Here we report that the commonly applied regimen of administration of 4 alternate day doses of 1mg Tamoxifen per mouse until 14 days prior to start of the actual experiment, in this case the induction of obstructive nephropathy by Unilateral Ureteral Obstruction (UUO), still attenuated fibrosis in female obstructed mouse kidneys, whereas this effect was not seen in male obstructed kidneys. Attenuation of fibrosis was accompanied by a reduction in nuclear ERα positivity despite absence of detectable levels of the active tamoxifen metabolite endoxifen throughout the UUO experiment. In conclusion, these results indicate that the Tamoxifen dosing regimen commonly applied in conditional gene targeting experiments might have prolonged confounding effects in female mice through attenuation of renal fibrosis independent of modulation of the expression of the targeted gene(s).