Animal Models Of Kidney Disease Research Articles

Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis.

Nephropathic cystinosis is a rare inherited lysosomal storage disorder caused by mutations in the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. From the standpoint of the kidneys, patients develop early-onset renal Fanconi syndrome and progressive chronic kidney disease. Current therapy with cysteamine delays but does not prevent kidney failure, and has significant side effects that limit adherence and reduce the quality of life of patients. We have tested biochemically and histologically the effects of ketogenic diet on kidney disease of two animal models of nephropathic cystinosis. When Ctns-/- mice were fed with ketogenic diet from 3 to 12 months of age, we observed significant nearly complete prevention of Fanconi syndrome, including low molecular weight proteinuria, glycosuria and polyuria. Compared to wild-type animals, BUN at 12 months was higher in cystinotic mice fed with standard diet (P<0.001), but not with ketogenic diet. At sacrifice, kidneys of knock out mice fed with ketogenic diet appeared macroscopically similar to those of wild type animals, which was reflected microscopically by a significant reduction of interstitial cell infiltration (CD3 and CD68 positive cells, P<0.01), of interstitial fibrosis (Masson and α-SMA staining, P< 0.001), and of apoptosis (cleaved caspase 3 levels; P<0.001), and by indirect evidence of restoration of a normal autophagic flux (SQSTM1/p62 and LC3-II expression, P<0.05). Beneficial effects of ketogenic diet on tubular function were also observed after mice were fed with this ketogenic diet from the age of 6 months to the age of 15 months, after they had developed proximal tubular dysfunction. Although slightly less pronounced, these results were replicated in Ctns-/- rats fed with ketogenic diet from 2 to 8 months of life. These results indicate significant mitigation of the kidney phenotype in cystinotic animals fed with ketogenic diet.

Renal-protective effects of Chinese medicinal herbs and compounds for diabetic kidney disease in animal models: protocol for systematic review and meta-analysis

BackgroundDiabetic kidney disease (DKD) is a common and severe complication of diabetes that can lead to end-stage renal disease with no cure. The first-line drugs recommended by clinical guidelines fail to achieve satisfactory effects for people with DKD. A Chinese herbal medicine Tangshen Qushi Formula (TQF) shows preliminary efficacy and safety in preserving renal function for people with DKD, but the effects on comprehensive renal outcomes remain unclear. We will conduct a systematic review and meta-analysis to evaluate the effects of TQF herbs and their compounds identified from ultra-high performance liquid chromatography-MS/MS in diabetic animal models with renal outcomes.MethodsThis protocol complies with the guideline Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We will include studies investigating the effects of TQF herbs and compounds on diabetic rats or mice with renal outcomes. Six electronic databases will be searched from their inception to February 2023. Quality assessment will be conducted using SYRCLE’s risk of bias tool. Standardized or weighted mean differences will be estimated for renal outcomes (creatinine, urea, proteinuria, histological changes, oxidative stress, inflammation, and kidney fibrosis). Data will be pooled using random-effects models. Heterogeneity across studies will be expressed as I2. Sensitivity analyses will explore treatment effects in adjusted models and within subgroups. Funnel plots and Egger’s test will be used to explore publication bias.DiscussionThe results of this review will provide valuable insights into the potential effects of TQF in managing DKD. The limitation is that the included studies will be animal studies from specific databases, and the interpretation of the findings must be cautious.Systematic review registrationPROSPERO CRD42023432895. Registered on 19 July 2023 (https://www.crd.york.ac.uk/PROSPERO/#recordDetails).

Pre-treatment with β-hydroxybutyrate mitigates cisplatin-induced acute kidney injury

β-Hydroxybutyrate (β-HB), the primary circulating ketone body, plays a dual role as both a metabolic fuel and an endogenous signaling molecule, offering diverse systemic benefits. Recent studies have highlighted the renoprotective effects of exogenous β-HB therapy in various animal models of kidney disease. In this investigation, our goal was to assess whether pre-treatment with exogenous β-HB could alleviate kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI). Prior to cisplatin administration, intraperitoneal administration of β-HB was carried out, and the groups were classified into four: Sham, β-HB, cisplatin, and β-HB + cisplatin. The tubular damage score and serum creatinine levels were significantly lower in the β-HB + cisplatin group compared to the cisplatin group. Furthermore, the expression of phosphorylated NF-κB, inflammatory cytokines, and the quantity of F4/80-positive macrophages in the β-HB + cisplatin group were reduced compared to those in the cisplatin group. Additionally, oxidative stress markers for DNA, protein, and lipid in the β-HB + cisplatin group were markedly diminished compared to those in the cisplatin group. The number of TUNEL-positive and cleaved caspase 3-positive tubular cells in the β-HB + cisplatin group was lower than in the cisplatin group. Pre-treating with exogenous β-HB effectively mitigated kidney damage by suppressing inflammation, oxidative stress, and tubular apoptosis in cisplatin-induced AKI. Therefore, exogenous β-HB as a pre-treatment emerges as a promising and novel strategy for preventing cisplatin-induced AKI.

Beyond 2D: A scalable and highly sensitive method for a comprehensive 3D analysis of kidney biopsy tissue.

The spatial organization of various cell populations is critical for the major physiological and pathological processes in the kidneys. Most evaluation of these processes typically comes from a conventional 2D tissue cross-section, visualizing a limited amount of cell organization. Therefore, the 2D analysis of kidney biopsy introduces selection bias. The 2D analysis potentially omits key pathological findings outside a 1- to 10-μm thin-sectioned area and lacks information on tissue organization, especially in a particular irregular structure such as crescentic glomeruli. In this study, we introduce an easy-to-use and scalable method for obtaining high-quality images of molecules of interest in a large tissue volume, enabling a comprehensive evaluation of the 3D organization and cellular composition of kidney tissue, especially the glomerular structure. We show that CUBIC and ScaleS clearing protocols could allow a 3D analysis of the kidney tissues in human and animal models of kidney disease. We also demonstrate that the paraffin-embedded human biopsy specimens previously examined via 2D evaluation could be applicable to 3D analysis, showing a potential utilization of this method in kidney biopsy tissue collected in the past. In summary, the 3D analysis of kidney biopsy provides a more comprehensive analysis and a minimized selection bias than 2D tissue analysis. Additionally, this method enables a quantitative evaluation of particular kidney structures and their surrounding tissues, with the potential utilization from basic science investigation to applied diagnostics in nephrology.

Animal Models of Kidney Disease: Challenges and Perspectives.

Kidney disease is highly prevalent and affects about 850 million people worldwide. It is also associated with high morbidity and mortality, and current therapies are incurable and often ineffective. Animal models are indispensable for understanding the pathophysiology of various kidney diseases and for preclinically testing novel remedies. In the last two decades, rodents continue to be the most used models for imitating human kidney diseases, largely due to the increasing availability of many unique genetically modified mice. Despite many limitations and pitfalls, animal models play an essential and irreplaceable role in gaining novel insights into the mechanisms, pathologies and therapeutic targets of kidney disease. In this review, we highlight commonly used animal models of kidney diseases by focusing on experimental acute kidney injury, chronic kidney disease, and diabetic kidney disease. We briefly summarize the pathological characteristics, advantages and drawbacks of some widely used models. Emerging animal models such as mini-pig, salamander, zebrafish and drosophila, as well as human-derived kidney organoids and kidney-on-a-chip are also discussed. Undoubtedly, careful selection and utilization of appropriate animal models is of vital importance in deciphering the mechanisms underlying nephropathies and evaluating the efficacy of new treatment options. Such studies will provide a solid foundation for future diagnosis, prevention and treatment of human kidney diseases.

#5592 THE SODIUM PHOSPHATE COTRANSPORTER NAPI-IIB IS UPREGULATED AND EXPRESSED DE NOVO IN KIDNEYS OF PATIENTS WITH CHRONIC KIDNEYS DISEASE

Abstract Background and Aims Renal reabsorption of phosphate is mediated by 3 main transporters located in the luminal brush border membrane of the proximal tubule, namely NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit2 (SLC20A2). The expression of all three proteins has been shown to be reduced in animal models of kidney disease [1]. Recently, we demonstrated that NaPi-IIb, a paralogue of the SLC34 subfamily that is mostly expressed in small intestine and lungs, is also expressed in the loop of Henle. Its mRNA expression is enhanced in rodent models of kidney injury. However, the expression of NaPi-IIb has not been characterized in humans and it is unknown whether NaPi-IIb is also upregulated in chronic kidney disease (CKD). Method In this study, we examined the localization of NaPi-IIa, IIb, and IIc in kidneys of control healthy individuals (kidney donors) (eGFR: 111.6 ± 22.9 ml/min/1.73m2) and patients with diabetic nephropathy (eGFR: 31.9 ± 7.7 ml/min/1.73m2), anti-glomerular basement membrane nephritis (anti-GMB) (eGFR: 27.2 ± 22.6 ml/min/1.73m2), and hypertensive nephropathy (eGFR: 31.5 ± 5.3 ml/min/1.73m2) by immunofluorescence. Moreover, we analyzed data from various transcriptome data bases from healthy individuals and patients with CKD. Results In kidneys from healthy donors, NaPi-IIb staining was restricted to thin and thick limbs of the loop of Henle, while AQP1 was observed in proximal tubules and descending thin limbs. NaPi-IIc was abundantly found in proximal tubule cells. In biopsies from patients, NaPi-IIb signal was also found in addition to thin and thick limbs in cells of the collecting duct and in many proximal tubules. In contrast, the staining of NaPi-IIc was reduced in all groups of patients with CKD. RNA expression data from the European Renal cDNA Bank (ERCB) confirmed our immunofluorescence findings. SLC34A2 (NaPi-IIb) mRNA was progressively more expressed in kidneys of patients with kidney disease of tubulointerstitial origin from CKD stages 1 to 5, while it was strongly upregulated from stage 4 onwards in CKD of glomerular origin. Single cell RNA sequencing data of patients with acute kidney injury and CKD [2] showed elevation of SLC34A2 expression in injured thick ascending limb, degenerative proximal tubule cells (14x higher, adj. p≪0.0001) (de novo expression), and descending thin limb (3.7x higher, adj. p≪0.0001). SLC34A1 (NaPi-IIa) expression levels were reduced in whole kidneys (ERCB data) and SLC34A1 and SLC34A3 expression also decreased in proximal tubule cells of patients with CKD. Conclusion The phosphate transporter NaPi-IIb is highly upregulated in kidneys from patients with various etiologies of CKD and its expression spreads to proximal tubule and collecting duct. In contrast, the expression of the main physiological phosphate transporters NaPi-IIa and NaPi-IIc is reduced in CKD. These findings may have implications for the development and maintenance of hyperphosphatemia in CKD patients and limit the use of specific NaPi-IIa and/or NaPi-IIc inhibitors in patients with CKD.

Diagnostic and prognostic biomarkers for tubulointerstitial fibrosis.

Renal fibrosis is the final common pathophysiological pathway in chronic kidney disease (CKD) regardless of the underlying cause of kidney injury. Tubulointerstitial fibrosis (TIF) is considered to be the key pathological predictor of CKD progression. Currently, the gold standard tool to identify TIF is kidney biopsy, an invasive method that carries risks. Non-invasive diagnostics rely on an estimation of glomerular filtration rate (eGFR) and albuminuria that assess kidney function, but these fail to accurately diagnose early CKD, and predict progressive decline in kidney function. In this review we summarize the current and emerging molecular biomarkers which have been studied in various clinical settings and in animal models of kidney disease and which correlate with the degree of TIF. We examine the potential of these biomarkers to non-invasively diagnose TIF and predict disease progression. We also examine the potential of novel technologies and non-invasive diagnostic approaches in assessing TIF. Limitations of current and potential biomarkers are discussed, and knowledge gaps are identified. Abstract figure legend The best predictor of chronic kidney disease (CKD) is tubulointerstitial fibrosis (TIF). Kidney biopsy is the gold standard diagnostic method for TIF, which is invasive. Non-invasive methods might involve assessing kidney function, identifying potential urinary and blood biomarkers, and using novel technologies. Assessing kidney function by measuring glomerular filtration rate and albuminuria has poor diagnostic and prognostic accuracy for TIF. In this review, we present current and potential soluble biomarkers and novel technologies and discuss their diagnostic and prognostic accuracies. This article is protected by copyright. All rights reserved.

The Role of Ketone Bodies in Various Animal Models of Kidney Disease

The kidney is a vital organ that carries out significant metabolic functions in our body. Due to the complexity of its role, the kidney is also susceptible to many disease conditions, such as acute kidney injury (AKI) and chronic kidney disease (CKD). Despite the prevalence and our increased understanding of the pathophysiology of both AKI and CKD as well as the transition of AKI to CKD, no well-established therapeutics have been applied clinically to these conditions, rendering an urgent need for a novel potential therapeutic target to be developed. In this article, we reviewed the function of ketone bodies in some common kidney conditions, such as drug-induced nephrotoxicity, ischemia and reperfusion injury, fibrosis development, diabetic kidney disease, kidney aging, hypertension, and CKD progression. All the selected studies reviewed were performed in animal models by primarily utilizing rodents, which also provide invaluable sources for future clinical applications. Ketone bodies have shown significant renal protective properties via attenuation of oxidative stress, increased expression of anti-inflammatory proteins, gene regulation, and a reduction of apoptosis of renal cells. A physiological level of ketone bodies could be achieved by fasting, a ketogenic diet, and an exogenous ketone supplement. Finally, the limitations of the long-term ketogenic diet were also discussed.

The Effects of TRPC6 Knockout in Animal Models of Kidney Disease.

Diseases that induce a loss of renal function affect a substantial portion of the world's population and can range from a slight decline in the glomerular filtration rate or microalbuminuria to complete kidney failure. Kidney disorders can be acute or chronic, but any significant reduction in renal function is associated with increased all-cause morbidity and mortality, especially when the conditions become chronic. There is an urgent need for new therapeutic approaches to slow or halt the progression of kidney disease. One potential target of considerable interest is the canonical transient receptor potential-6 (TRPC6) channel. TRCP6 is a cationic channel with a significant permeability to Ca2+. It is expressed in several tissues, including in multiple cell types of the kidney in glomeruli, microvasculature, and tubules. Here, we will describe TRPC6 channels and their roles in signal transduction, with an emphasis on renal cells, and the studies implicating TRPC6 channels in the progression of inherited and acquired kidney diseases. We then describe studies using TRPC6 knockout mice and rats subjected to treatments that model human diseases, including nephrotic syndromes, diabetic nephropathy, autoimmune glomerulonephritis, and acute kidney injuries induced by renal ischemia and by obstruction of the urinary tract. TRPC6 knockout has been shown to reduce glomerular manifestations of disease in several of these models and reduces renal fibrosis caused by urinary tract obstruction. TRPC6 knockout has proven to be less effective at reducing diabetic nephropathy in mouse and rat models. We also summarize the implications of these studies for drug development.

Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study.

Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

Involvement of Inflammasome Components in Kidney Disease.

Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.

Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury.

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression. Furthermore, evidence in human and experimental animal studies have found that decreased EET levels contribute to hypertension and kidney diseases. Consequently, EET mimics/analogs have been developed as a potential therapeutic for hypertension and acute and chronic kidney diseases. Their development has resulted in EET analogs that are orally active with favorable pharmacological profiles. Analogs for 8,9-EET, 11,12-EET, and 14,15-EET have been tested in several hypertension and kidney disease animal models. More recently, kidney targeted EET analogs have been synthesized and tested against drug-induced nephrotoxicity. Experimental evidence has demonstrated compelling therapeutic potential for EET analogs to oppose cardiovascular and kidney diseases. These EET analogs lower blood pressure, decrease kidney inflammation, improve vascular endothelial function, and decrease kidney fibrosis and apoptosis. Overall, these preclinical studies support the likelihood that EET analogs will advance to clinical trials for hypertension and associated comorbidities or acute and chronic kidney diseases.

Folic acid-induced animal model of kidney disease.

The kidneys are a vital organ that is vulnerable to both acute kidney injury (AKI) and chronic kidney disease (CKD) which can be caused by numerous risk factors such as ischemia, sepsis, drug toxicity and drug overdose, exposure to heavy metals, and diabetes. In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD, there is still no available therapeutics that can be used to combat kidney disease effectively, highlighting an urgent need to further study the pathological mechanisms underlying AKI, CKD, and AKI progression to CKD. In this regard, animal models of kidney disease are indispensable. This article reviews a widely used animal model of kidney disease, which is induced by folic acid (FA). While a low dose of FA is nutritionally beneficial, a high dose of FA is very toxic to the kidneys. Following a brief description of the procedure for disease induction by FA, major mechanisms of FA‐induced kidney injury are then reviewed, including oxidative stress, mitochondrial abnormalities such as impaired bioenergetics and mitophagy, ferroptosis, pyroptosis, and increased expression of fibroblast growth factor 23 (FGF23). Finally, application of this FA‐induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given that this animal model is simple to create and is reproducible, it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease.

Gasotransmitters for the Therapeutic Prevention of Hypertension and Kidney Disease.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), three major gasotransmitters, are involved in pleiotropic biofunctions. Research on their roles in hypertension and kidney disease has greatly expanded recently. The developing kidney can be programmed by various adverse in utero conditions by so-called renal programming, giving rise to hypertension and kidney disease in adulthood. Accordingly, early gasotransmitter-based interventions may have therapeutic potential to revoke programming processes, subsequently preventing hypertension and kidney disease of developmental origins. In this review, we describe the current knowledge of NO, CO, and H2S implicated in pregnancy, including in physiological and pathophysiological processes, highlighting their key roles in hypertension and kidney disease. We summarize current evidence of gasotransmitter-based interventions for prevention of hypertension and kidney disease in animal models. Continued study is required to assess the interplay among the gasotransmitters NO, CO, and H2S and renal programming, as well as a greater focus on further clinical translation.

Targeted Drug Delivery Systems for Kidney Diseases.

Kidney diseases have gradually become a global health burden. Along with the development of nanotechnology, many hybrids or nanomaterials have been utilized to promote treatment efficiency with negligible side effects. These therapeutic agents have been successfully applied in many fields. In particular, some efforts have also been made to ameliorate the treatment of kidney diseases through targeted delivery nanomaterials. Though most of the delivery systems have not yet been transmitted into clinical use or even still at an early stage, they have shown great potential in carrying immunosuppressants like tacrolimus and triptolide, antioxidants, or siRNAs. Excitingly, some of them have achieved significant treatment effectiveness and reduced systemic side effect in kidney disease animal models. Here, we have reviewed the recent advances and presented nanotherapeutic devices designed for kidney targeted delivery.

Subtotal Nephrectomy as a Model of Chronic Kidney Disease: A Systematic Review

Background: Subtotal nephrectomy (5/6 nephrectomy) is one of the most widely used animal models for modifying chronic kidney disease. Animal models of kidney disease play an important role to understand pathophysiology, progressivity, and therapies for the disease. The development of animal models that mimic the conditions in human disease is still a challenge. Methods: We conducted a systematic search in the main biomedical databases MEDLINE (PubMed) and the Directory of Open Access Journals (DOAJ)Conclusion: The subtotal nephrectomy procedure is a good model for chronic kidney disease. The kidney damage on this model most closely mimics with kidney damage in humans. This procedure used to remove or destroys 5/6 parts of the kidney, leaving only 1/3 of the kidney mass. There are variations to this procedure. Variations included in the type of incision, the location of the uninephrectomy, the type of ligase/ablation, the operation stage (one or two steps), the length of time between 2 operating procedures, the length of time for observation, and the type of animal used. Variations procedure in subtotal nephrectomy model have different effects on biochemical parameters, morphology, and markers of kidney damage.

Hypertension in an Animal Model of Kidney Disease is not Dependent on the Short‐Term Actions of Endogenous Tumour Necrosis Factor‐α in the SFO

Introduction The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by the overactivation of the subfornical organ (SFO). Circulating proinflammatory cytokines, namely tumour necrosis factor-α (TNFα), are suggested to act in the central nervous system to produce an increase in neuronal excitability. As circulating cytokines are increased in kidney disease, we hypothesised that TNFα acts on the SFO to increase neuronal activity, therefore contributing to the development of hypertension. Methods Urethane anaesthetised Lewis control (n=18 total) and LPK (n=18 total) rats were instrumented to record blood pressure and perform microinjections of TNFRI neutralising antibody (1ng/50nl) or minocycline (0.5µg/50nl), an inhibitor of microglial activation, followed by a GABAa agonist (10mM isoguvacine) into the SFO. Results Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK rats (9±2mmHg vs 3±4mmHg peak change from baseline, P=0.0004). Acute inhibition of local TNFα by microinjection of a TNFRI neutralising antibody into the SFO did not reduce mean arterial blood pressure in Lewis control or LPK rats (1±1mmHg vs -1±1mmHg change from baseline, P=0.78). Similarly, acute non-specific blockade of proinflammatory cytokines by microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK rats (-1±1mmHg vs -1±1mmHg change from baseline, P=0.98). Microinjection of a GABAa agonist into the SFO caused a significant depressor response that was not altered by the pre-treatment with a microinjection of TNFRI neutralising antibody in either strain (P>0.05), demonstrating that pre-treatment did alter the tonic activation of neurons within the SFO. Interestingly, pre-treatment with a microinjection of minocycline increased the tonic activation in the LPK (P=0.04), but not Lewis (P=0.15), as indicated by the increased depressor response to GABAa agonist microinjection. Conclusions Overall, these findings demonstrate that although the hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of blood pressure is not dependent on the actions of endogenous TNFα or generalised microglial and neuronal activation by proinflammatory cytokines in the SFO.

Finerenone – are we there yet with a non-steroidal mineralocorticoid receptor antagonist for the treatment of diabetic chronic kidney disease?

ABSTRACT Introduction: Chronic kidney disease occurs in 40% of subjects with diabetes and increases the risk of cardiovascular death three-fold, compared to having diabetes alone. The non-steroidal mineralocorticoid receptor antagonist finerenone protects against chronic kidney disease in animal models. Areas covered: This evaluation is of a phase 3 trial of finerenone; Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD). In FIDELIO-DKD, finerenone reduced the primary composite outcome of kidney failure, a sustained decrease of at least 40% in eGFR over four weeks, or death from renal causes, from 21.1% to 17.8%, with a good safety profile. Expert opinion: Finerenone is an effective mineralocorticoid receptor antagonist for the treatment of diabetic chronic kidney disease. Recently, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporters 2 (SGLT-2) inhibitors have been added to the list of medicines for use in subjects with this condition. Although finerenone has a different mechanism of action to these medicines, it will need to be tested and shown to be effective in presence of these medicines in diabetic kidney disease, prior to widespread use.

T helper 17 cells in the pathophysiology of acute and chronic kidney disease.

Both acute and chronic kidney disease have a strong underlying inflammatory component. This review focuses primarily on T helper 17 (Th17) cells as mediators of inflammation and their potential to modulate acute and chronic kidney disease. We provide updated information on factors and signaling pathways that promote Th17 cell differentiation with specific reference to kidney disease. We highlight numerous clinical studies that have investigated Th17 cells in the setting of human kidney disease and provide updated summaries from various experimental animal models of kidney disease indicating an important role for Th17 cells in renal fibrosis and hypertension. We focus on the pleiotropic effects of Th17 cells in different renal cell types as potentially relevant to the pathogenesis of kidney disease. Finally, we highlight studies that present contrasting roles for Th17 cells in kidney disease progression.

Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling.

The global burden of chronic kidney disease (CKD) intertwined with cardiovascular disease has become a major health problem. Oxidative stress (OS) plays an important role in the pathophysiology of CKD. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) antioxidant system plays a critical role in kidney protection by regulating antioxidants during OS. Heme oxygenase-1 (HO-1), one of the targets of Nrf2-ARE, plays an important role in regulating OS and is protective in a variety of human and animal models of kidney disease. Thus, activation of Nrf2-HO-1 signaling may offer a potential approach to the design of novel therapeutic agents for kidney diseases. In this review, we have discussed the association between OS and the pathogenesis of CKD. We propose Nrf2-HO-1 signaling-mediated cell survival systems be explored as pharmacological targets for the treatment of CKD and have reviewed the literature on the beneficial effects of small molecule natural products that may provide protection against CKD.