Introduction The pathogenesis of aging nephropathy is yet to be elucidated. Intrarenal Angiotensin-II (AngII) and activation of the NF-κB and NLRP3 inflammasome pathways exert a relevant pathogenic role in the progression of chronic kidney disease (CKD). We sought to investigate whether monotherapy with Losartan and combined treatment with Losartan and the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) would attenuate experimental aging nephropathy. Materials and Methods Forty adult Male Munich-Wistar rats were distributed among four groups: 12M (n=10), untreated 12-month-old rats; 15M (n=10), untreated 15-month-old rats; 15MLos (n=8), rats receiving Losartan (50 mg/kg/d) and 15MLos+PDTC (n=8), rats receiving Losartan and PDTC (60 mg/kg/d). All treatments were given by mouth from 12 to 15 months of age. Results Group 15M exhibited slightly decreased tail-cuff pressure, and marked increase in albuminuria, sclerotic glomeruli, cortical collagen-1 deposition and infiltration by myofibroblasts, AngII-positive cells and proinflammatory M1 macrophages, whereas the amount of anti-inflammatory M2 macrophages was reduced. In addition, the renal abundance of TLR4, nuclear p65 and IL-6 was increased, indicating activation of the NF-κB pathway, without evidence of simultaneous activation of the NLRP3 cascade. Losartan treatment decreased cortical collagen-1 deposition, myofibroblasts and AngII-positive cells, and partially restored renal M2, but had no significant effect on albuminuria, glomerulosclerosis or NF-κB activation. Combined Losartan+PDTC prevented all the observed abnormalities. Discussion/conclusion Simultaneous blockade of renal AngII and inhibition of the NF-κB pathway may represent a novel alternative to limit the decline of renal function with age.

An anoctamin 4 (ANO4) mutation was identified in dogs with calcium oxalate (CaOx) stones via GWAS, and the content of ANO4 is decreased in urinary extracellular vesicles of human CaOx stone formers. ANO proteins are Ca2+-activated Clchannels and/or Ca2+-activated phospholipid scramblases. In addition to these functions, the homolog of ANO4 in Drosophila, subdued, has been shown to play a role in host defense against gram-negative bacteria. Uropathogenic E. coli (UPEC) increases intrarenal CaOx crystallization in mammals.

EDITORIAL article Front. Pharmacol., 09 January 2024Sec. Renal Pharmacology Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1362010

The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis.

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.

Tissue hypoxia has been pointed out as a major pathogenic factor in chronic kidney disease (CKD). However, epidemiological and experimental evidence inconsistent with this notion has been described. We have previously reported that chronic exposure to low ambient Po2 promoted no renal injury in normal rats and in rats with 5/6 renal ablation (Nx) unexpectedly attenuated renal injury. In the present study, we investigated whether chronic exposure to low ambient Po2 would also be renoprotective in two additional models of CKD: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. In both models, normobaric ambient hypoxia attenuated the development of renal injury and inflammation. In addition, renal hypoxia limited the activation of NF-κB and NOD-like receptor family pyrin domain containing 3 inflammasome cascades as well as oxidative stress and intrarenal infiltration by angiotensin II-positive cells. Renal activation of hypoxia-inducible factor (HIF)-2α, along with other adaptive mechanisms to hypoxia, may have contributed to these renoprotective effects. The present findings may contribute to unravel the pathogenesis of CKD and to the development of innovative strategies to arrest its progression.NEW & NOTEWORTHY Hypoxia is regarded as a major pathogenic factor in chronic kidney disease (CKD). In disagreement with this view, we show here that sustained exposure to low ambient Po2 lessened kidney injury and inflammation in two CKD models: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. Together with our previous findings in the remnant kidney, these observations indicate that local changes elicited by hypoxia may exert renoprotection in CKD, raising the prospect of novel therapeutic strategies for this disease.

Fibrillin-1 is a pivotal structural component of the kidney’s glomerulus and peritubular tissue. Mutations in the fibrillin-1 gene result in Marfan syndrome (MFS), an autosomal dominant disease of the connective tissue. Although the kidney is not considered a classically affected organ in MFS, several case reports describe glomerular disease in patients. Therefore, this study aimed to characterize the kidney in the mgΔ lpn -mouse model of MFS. Affected animals presented a significant reduction of glomerulus, glomerulus-capillary, and urinary space, and a significant reduction of fibrillin-1 and fibronectin in the glomerulus. Transmission electron microscopy and 3D-ultrastructure analysis revealed decreased amounts of microfibrils which also appeared fragmented in the MFS mice. Increased collagen fibers types I and III, MMP-9, and α-actin were also observed in affected animals, suggesting a tissue-remodeling process in the kidney. Video microscopy analysis showed an increase of microvessel distribution coupled with reduction of blood-flow velocity, while ultrasound flow analysis revealed significantly lower blood flow in the kidney artery and vein of the MFS mice. The structural and hemodynamic changes of the kidney indicate the presence of kidney remodeling and vascular resistance in this MFS model. Both processes are associated with hypertension which is expected to worsen the cardiovascular phenotype in MFS.

Anoctamins (ANO) are activated by intracellular Ca 2+ and function as phospholipid scramblases and/or Cl - channels. ANO4 is mutated in miniature schnauzers with calcium oxalate stones (CaOx), and ANO4 protein in urinary extracellular vesicles is decreased in human CaOx stone formers. In Drosophila Malpighian tubules (MT), subdued (ANO4-homolog) functions as Ca 2+ -activated Cl - channel, scramblase, and plays a role in host defense against gram-negative bacteria. Increasing evidence shows the participation of bacteria in urinary stone formation in humans. We used a Drosophila avatar to investigate whether subdued changes CaOx crystallization and if crystallization increases with bacterial infection.Uro:Gal4 flies were crossed with UAS:subdued-RNAi flies to knockdown (KD) subdued in MT principal cells (PC) or with w 1118 flies to generate normal controls (WT). F1 generation underwent CaOx crystallization in association or not with uropathogenic E. coli (UPEC) infection. In vivo, flies were fed on diet supplemented with 20mM sodium Ox (NaOx) + UPEC:eGFP for 4 days. For ex vivo assays, dissected MTs were submerged in solution containing 10mM NaOx+ UPEC:eGFP for 90 minutes. subdued-KD in PC reduced subdued mRNA by 56% in MT. Neither crystal number nor size were changed by subdued-KD after prolonged NaOx feeding. However, when UPEC is introduced with the NaOx diet, subdued-KD flies exhibited a large bacterial presence in MT lumen and produced enlarged CaOx crystals compared to WT flies. Similar augmented presence of UPEC in subdued-KD MTs was observed during ex vivo assays. Short-term exposure to NaOx+UPEC resulted in increased number of crystals in subdued-KD MTs compared to WT MTs, but no difference was observed in crystal size.Fly cell atlas ( flycellatlas.org ) revealed that subdued is also found in MT stellate cells (SC; water and Cl - secretion). C724:Gal4>UAS:subdued-RNAi flies were used to assess the effect of subdued-KD in SC. This s ubdued-KD slightly increased bacterial infection but did change CaOx crystallization in MTs after 4 days of NaOx+UPEC feeding.The presence of subdued in PC limits CaOx crystals formation and aggregation through reducing bacterial invasion in the MT lumen. These Drosophila results suggest a role for ANO4 in bacterial-related human and dog kidney stone formation. Future experiments will determine whether other functional aspects of subdued affect CaOx crystallization. U54-DK100227, R01-DK092408, FAPESP (2022/01226-1), Mayo Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Seminal works have now revealed the gut microbiota is connected with several diseases, including renal disorders. The balance between optimal and dysregulated host-microbiota interactions has completely changed our understanding of immunity and inflammation. Kidney injury is associated with accumulation of uremic toxins in the intestine, augmented intestinal permeability, and systemic inflammation. Intestinal bacteria can signal through innate receptors and induce immune cell activation in the lamina propria and release of inflammatory mediators into the bloodstream . But the gut microbiota can also modulate immune functions through soluble products as short-chain fatty acids (SCFAs). The three most common SCFAs are propionate, butyrate, and acetate, which can signal through specific G-protein coupled receptors (GPCRs), such as GPR43, GPR41, and GPR109a, expressed on the surface of epithelial, myeloid, endothelial, and immune cells, among others. The triggered signaling can change cell metabolism, immune cell activation, and cell death. In this study, we reviewed the gut-kidney axis, how kidney cells can sense SCFAs, and its implication in kidney diseases.

In recent decades, there has been a progressive increase in the prevalence of obesity and chronic kidney disease. Renal lipotoxicity has been associated with obesity. Although lipids play fundamental physiological roles, the accumulation of lipids in kidney cells may cause dysfunction and/or renal fibrosis. Adipose tissue that exceeds their lipid storage capacity begins to release triglycerides into the bloodstream that can get stored in several organs, including the kidneys. The mechanisms underlying renal lipotoxicity involve intracellular lipid accumulation and organelle dysfunction, which trigger oxidative stress and inflammation that consequently result in insulin resistance and albuminuria. However, the specific pathways involved in renal lipotoxicity have not yet been fully understood. We aimed to summarize the current knowledge on the mechanisms by which lipotoxicity affects the renal morphology and function in experimental models of obesity. The accumulation of fatty acids in tubular cells has been described as the main mechanism of lipotoxicity; however, lipids and their metabolism also affect the function and the survival of podocytes. In this review, we presented indication of mitochondrial, lysosomal and endoplasmic reticulum alterations involved in kidney damage caused by obesity. The kidney is vulnerable to lipotoxicity, and studies of the mechanisms underlying renal injury caused by obesity can help identify therapeutic targets to control renal dysfunction.

Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disease (CKD). The mechanisms underlying this transition are unclear and may involve sustained activation of renal innate immunity, with resulting renal inflammation and fibrosis. We investigated whether the NF-κB system and/or the NLRP3 inflammasome pathway remain activated after the resolution of AKI induced by gentamicin (GT) treatment, thus favoring the development of CKD. Male Munich-Wistar rats received daily subcutaneous injections of GT, 80 mg/kg, for 9 days. Control rats received vehicle only (NC). Rats were studied at 1, 30, and 180 days after GT treatment was ceased. On Day 1, glomerular ischemia (ISCH), tubular necrosis, albuminuria, creatinine retention, and tubular dysfunction were noted, in association with prominent renal infiltration by macrophages and myofibroblasts, along with increased renal abundance of TLR4, IL-6, and IL1β. Regression of functional and structural changes occurred on Day 30. However, the renal content of IL-1β was still elevated at this time, while the local renin-angiotensin system remained activated, and interstitial fibrosis became evident. On Day 180, recurring albuminuria and mild glomerulosclerosis were seen, along with ISCH and unabated interstitial fibrosis, whereas macrophage infiltration was still evident. GT-induced AKI activates innate immunity and promotes renal inflammation. Persistence of these abnormalities provides a plausible explanation for the transition of AKI to CKD observed in a growing number of patients.

PURPOSE OF REVIEW Uric acid is produced after purine nucleotide degradation, upon xanthine oxidase catalytic action. In the evolutionary process, humans lost uricase, an enzyme that converts uric acid into allantoin, resulting in increased serum uric acid levels that may vary according to dietary ingestion, pathological conditions, and other factors. Despite the controversy over the inflammatory role of uric acid in its soluble form, crystals of uric acid are able to activate the NLRP3 inflammasome in different tissues. Uric acid, therefore, triggers hyperuricemic-related disease such as gout, metabolic syndrome, and kidney injuries. The present review provides an overview on the role of uric acid in the inflammasome-mediated kidney damage. RECENT FINDINGS Hyperuricemia is present in 20-35% of patients with chronic kidney disease. However, whether this increased circulating uric acid is a risk factor or just a biomarker of renal and cardiovascular injuries has become a topic of intense discussion. Despite these conflicting views, several studies support the idea that hyperuricemia is indeed a cause of progression of kidney disease, with a putative role for soluble uric acid in activating renal NLRP3 inflammasome, in reprograming renal and immune cell metabolism and, therefore, in promoting kidney inflammation/injury. SUMMARY Therapies aiming to decrease uric acid levels prevent renal NLRP3 inflammasome activation and exert renoprotective effects in experimental kidney diseases. However, further clinical studies are needed to investigate whether reduced circulating uric acid can also inhibit the inflammasome and be beneficial in human conditions.

High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammatory mediators. We investigated whether the NF-κB pathway is involved in the pathogenesis and progression of experimental diabetic kidney disease (DKD) in a model of long-term type 1 diabetes mellitus (DM). Adult male Munich-Wistar rats underwent DM by a single streptozotocin injection, and were kept moderately hyperglycemic by daily insulin injections. After 12 months, two subgroups - progressors and non-progressors - could be formed based on the degree of glomerulosclerosis. Only progressors exhibited renal TLR4, NF-κB and IL-6 activation. This scenario was already present in rats with short-term DM (2 months), at a time when no overt glomerulosclerosis can be detected. Chronic treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-κB or IL-6, without interfering with blood glucose. PDTC prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-κB p65 component was detected in sclerotic glomeruli and inflamed interstitial areas in biopsy material from patients with type 1 DM. These observations indicate that the renal NF-κB pathway plays a key role in the development and progression of experimental DKD, and can become an important therapeutic target in the quest to prevent the progression of human DKD.

Increasing evidence shows the essential participation of gut microbiota in human health and diseases by shaping local and systemic immunity. Despite an accumulating body of studies showing that chronic kidney disease (CKD) is closely associated with disturbances in the composition of gut microbiota, it remains unclear the importance of gut microbiota in the onset and development of CKD. For the purpose of untangling the role of gut microbiota in CKD, gut microbiota was depleted with a pool of broad-spectrum antibiotics in mice submitted to unilateral ureteral obstruction (UUO). Depletion of gut microbiota significantly decreased levels of proinflammatory cytokines and fibrosis markers, attenuating renal injury. Additionally, to study whether the pathogenic role of gut microbiota is dependent of microbial-host crosstalk, we generated mice lacking Myd88 (myeloid differentiation primary response gene 8) expression in intestinal epithelial cells (IECs) and performed UUO. The absence of Myd88 in IECs prevented a bacterial burden in mesenteric lymph nodes as observed in WT mice after UUO and led to lower expression of proinflammatory cytokines and chemokines, reducing deposition of type I collagen and, ultimately, attenuating renal damage. Therefore, our results suggest that the presence of gut microbiota is crucial for the development of CKD and may be dependent of Myd88 signaling in IECs, which appears to be essential to maturation of immune cells intimately involved in aggravation of inflammatory scenarios.