Renal Failure In Humans Research Articles

Sequencing Approaches for Understanding the Pathogenic Features in Leptospira Genome

Leptospirosis is a zoonotic illness caused by a bacterial spirochaete belonging to the genus Leptospira that induces renal failure in humans. This bacterium has high pathogenicity and can even cause death. As a result, research into the pathogenic mechanism of this organism is essential. Sequencing can be performed to understand the evolution and characteristics of an organism. Sequencing technologies like Sanger sequencing, Illumina sequencing, and recent technologies like MinION nanopore sequencing can be performed to study the whole genome of leptospiral strains. Based on whole genome sequencing, pathogenic characteristics and pathways involved during disease infection can be investigated. Identification of pathogenic features in the whole genome of Leptospira sp. may enable certain gene modifications or the development of potential vaccines to eradicate the disease. This review is an overview of various sequencing approaches and highlights the comparison of genome features present in pathogenic leptospires and saprophytic leptospires.

Glomerulotubular pathology in dogs with subclinical ehrlichiosis.

Subclinical stage of ehrlichiosis is characterized by absence of clinical or laboratory alterations; however, it could lead to silent glomerular/tubular changes and contribute significantly to renal failure in humans and animals. The aim of this study was to evaluate glomerular and tubular alterations in dogs with subclinical ehrlichiosis. We evaluated renal biopsies of 14 bitches with subclinical ehrlichiosis and 11 control dogs. Samples were obtained from the left kidney, and the tissue obtained was divided for light microscopy, immunofluorescence, and transmission electron microscopy. Abnormalities were identified by light microscopy in 92.9% of dogs with ehrlichiosis, but not in any of the dogs of the control group. Mesangial cell proliferation and synechiae (46.1%) were the most common findings, but focal segmental glomerulosclerosis and ischemic glomeruli (38.4%), focal glomerular mesangial matrix expansion (30.7%), mild to moderate interstitial fibrosis and tubular atrophy (23%), and glomerular basement membrane spikes (23%) were also frequent in dogs with ehrlichiosis. All animals with ehrlichiosis exhibited positive immunofluorescence staining for immunoglobulins. Transmission electron microscopy from dogs with ehrlichiosis revealed slight changes such as sparse surface projections and basement membrane double contour. The subclinical phase of ehrlichiosis poses a higher risk of development of kidney damage due to the deposition of immune complexes.

Interactions between Babesia microti merozoites and rat kidney cells in a short-term in vitro culture and animal model

Babesiosis is one of the most common infections in free-living animals and is rapidly becoming significant among human zoonoses. Cases of acute renal failure in humans caused by Babesia spp. have been described in the literature. The kidneys are characterised by intense blood flow through the blood vessels, which increases the likelihood of contact with the intra-erythrocyte parasite. The aim of this study was to observe the influence of B. microti (ATCC 30221) on renal epithelial cells in vitro cultured (NRK-52E line) and Wistar rats’ kidney. Both NRK-52E cells and rats’ kidney sections were analysed by light microscopy, transmission electron microscopy (TEM) and fluorescence in situ hybridization (FISH). Necrotic changes in renal epithelial cells have been observed in vitro and in vivo. In many cross-sections through the rats’ kidney, adhesion of blood cells to the vascular endothelium, accumulation of erythrocytes and emboli were demonstrated. In NRK-52E culture, elements with a distinctly doubled cell membrane resembling B. microti were found inside the cytoplasm and adjacent to the cell layer. The study indicates a chemotactic tendency for B. microti to adhere to the renal tubules' epithelium, a possibility of piroplasms entering the renal epithelial cells, their proliferation within the cytoplasm and emboli formation.

Hyperphosphatemia with Elevated Serum FGF-23 and PTH, Reduced Calcitriol, and Normal FGF7 Concentrations Characterizes Chronic Renal Failure in Humans

Hyperphosphatemia with Elevated Serum FGF-23 and PTH, Reduced Calcitriol, and Normal FGF7 Concentrations Characterizes Chronic Renal Failure in Humans

Numb ameliorates necrosis and inflammation in acute kidney injury induced by cisplatin

Cisplatin induces acute renal failure in humans and mice.Tubular apoptosis, necrosis and inflammation are the primary pathogenesis of cisplatin-induced acute kidney injury(AKI). We previously reported that the depletion of Numb from proximal tubules exacerbates tubular cells apoptosis in cisplatin-induced AKI, however, the role of Numb in tubular necrosis and renal inflammation in cisplatin-induced AKI remains unclear. A mouse model of AKI was produced by cisplatin intraperitoneally injection in mice from proximal tubule-specific depletion of Numb (PT-Nb-KO) and their wild-type littermates (PT-Nb-WT) respectively. Renal Numb expression was determined by Western blotting. Renal morphological damage was examined by hematoxylin and eosin staining (H&E staining). Tubular necrosis was evaluated by histological study and the protein level of renal Mixed lineage kinase domain-like protein (MLKL) which is a molecular marker of necrosis. Leukocyte infiltration and pro-inflammatory cytokines was determined by immunostaining and quantitative real-time PCR (qRT-PCR) respectively.The protein level of Numb was dramatically decreased in kidneys of PT-Nb-KO mice compared with PT-Nb-WT mice. After cisplatin injection, a significant increase of tubular injury score and the protein level of renal MLKL were detected in PT-Nb-KO mice compared with those in PT-Nb-WT. In addition, the number of F4/80-positve and CD3-positive cells, markers for macrophages and neutraphils respectively, showed significantly increased in kidneys from PT-Nb-KO mice compared with those in PT-Nb-WT mice. Consistently, the gene expression of pro-inflammatory cytokines including TNF-α and MCP-1 in the kidneys was higher in PT-Nb-KO mice than those in PT-Nb-WT mice. Numb play additional protective role in cisplatin-induced AKI through ameliorating tubular necrosis and renal inflammation besides attenuating cisplatin-induced tubular apoptosis.

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents

ObjectivePatients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise...

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2\u2212/\u2212 phenotype

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α−androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

SHROOM3 is a novel component of the planar cell polarity pathway whose disruption causes congenital heart disease

Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite CHD frequency, the etiology remains mostly unknown. Understanding CHD genetics and elucidating disease mechanism will help establish prognosis, identify comorbidity risks, and develop targeted therapies. CHD often results from disrupted cytoarchitecture and signaling pathways. We have identified a novel CHD candidate SHROOM3, a protein associated with the actin cytoskeleton and the Wnt/Planar Cell Polarity (PCP) signaling pathway. SHROOM3 induces actomyosin constriction within the apical side of cells and is implicated in neural tube defects and chronic renal failure in humans. A recent study demonstrated that SHROOM3 interacts with Dishevelled2 (DVL2), a component of the PCP signaling pathway, suggesting that SHROOM3 serves as an important link between acto-myosin constriction and PCP signaling. PCP signaling establishes cell polarity required for multiple developmental processes, and is required for cardiac development. In Preliminary data we utilized a Shroom3 gene-trap mouse (Shroom3gt/gt) to demonstrated that SHROOM3 disruption leads to cardiac defects phenocopy PCP disruption. We also demonstrate that patients with CHD phenotypes have rare and potentially damaging SHROOM3 variants within SHROOM3’s PCP-binding domain. We hypothesize SHROOM3 is a novel terminal effector of PCP signaling, and disruption is a novel contributor to CHD. To test this, we assessed genetic interaction between SHROOM3 and PCP during cardiac development and the ultimate effect on cell structure and movement. Heterozygous Shroom3+/gt mice and heterozygous Dvl2 +/- mice are phenotypically normal. We demonstrated genetic interaction between SHROOM3 and PCP signaling by generating compound heterozygous Shroom3+/gt ;Dvl2 +/- mice and identifying a Double Outlet Right Ventricle and Ventricular Septal Defect in one embryo. We also observed fewer compound heterozygous mice than anticipated by Mendelian rations (observed: 18.4%; expected: 25%; n=76), suggesting potential lethality in utero. Immunohistochemistry demonstrates disrupted actomyosin in the SHROOM3gt/gt mice, characteristic of PCP disruption. These data help strengthen SHROOM3 as a novel CHD candidate gene and a component of the PCP Signaling pathway. Further characterization of this gene is important for CHD diagnosis and therapeutic development.

Mechanisms underlying Enterohaemorrhagic Escherichia coli O157: H7 manipulation of the bovine cellular immune response

Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 can cause haemorrhagic diarrhoea and potentially fatal renal failure in humans. Ruminants are considered the primary reservoir for human infection. Studies investigating the response of cattle to colonization generally focus on humoral immunity, leaving the role of cellular immunity unclear. These bacteria colonise their host by tight attachment to the epithelium, using a type three secretion system to inject a cocktail of effectors into the host cell. Injected effectors manipulate the innate response in several ways to promote bacterial persistence. Transcriptional profiling of responses at the terminal rectum, the primary site of colonisation in cattle, reveals a bias towards a T-helper type 1 response, indicating that cellular immunity may be involved in bacterial clearance. Mathematical modelling also indicates that injected effectors have a reduced human MHC-I epitope density, whilst structural bacterial proteins do not. This implies that host cellular immune responses target injected effectors and have exerted selective pressure on their evolution. My on-going research is examining the expression of MHC-I on the surface of cultured bovine epithelial cells following infection with E. coli O157. Initial results demonstrate a decrease in MHC-I surface expression during EHEC O157 colonisation after three hours. The basis of this reduction is being investigated using defined mutants in type three secretion genes. The longer-term objective is to use peptide elution and mass spectrometry to examine the presentation of effector protein peptides and determine whether E. coli O157 has evolved to interfere with this process.

Identification and prevalence of in vivo-induced genes in enterohaemorrhagic Escherichia coli

ABSTRACTEnterohaemorrhagic Escherichia coli (EHEC) are food-borne pathogens responsible for bloody diarrhoea and renal failure in humans. While Shiga toxin (Stx) is the cardinal virulence factor of EHEC, its production by E. coli is not sufficient to cause disease and many Shiga-toxin producing E. coli (STEC) strains have never been implicated in human infection. So far, the pathophysiology of EHEC infection is not fully understood and more knowledge is needed to characterize the “auxiliary” factors that enable a STEC strain to cause disease in humans. In this study, we applied a recombinase-based in vivo expression technology (RIVET) to the EHEC reference strain EDL933 in order to identify genes specifically induced during the infectious process, using mouse as an infection model. We identified 31 in vivo-induced (ivi) genes having functions related to metabolism, stress adaptive response and bacterial virulence or fitness. Eight of the 31 ivi genes were found to be heterogeneously distributed in EHEC strains circulating in France these last years. In addition, they are more prevalent in strains from the TOP seven priority serotypes and particularly strains carrying significant virulence determinants such as Stx2 and intimin adhesin. This work sheds further light on bacterial determinants over-expressed in vivo during infection that may contribute to the potential of STEC strains to cause disease in humans.

Use of pulsed field gel electrophoresis genetic typing for tracing contamination with virulent Escherichia coli O157:H7 in beef-cattle producing farms

E. coli O157:H7 is an important causative agent of a variety of foodborne infections including hemorrhagic colitis (HC), hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) that may lead to renal failure in humans. The main source of infection is contaminated food of animal origin and a number of animal species especially cattle have been associated with this pathogen. Contamination usually occurs when faeces of animals get into contact with carcass during slaughtering. The aim of the present study was to determine the virulence profiles and genetic relationships of E. coli O157:H7 strains isolated from cattle some commercial farms in the North West Province, South Africa. A total of 260 faecal samples were collected from eight farms over a six-month period and assessed for the presence of E. coli O157:H7 through PCR analysis. Bacteria 16S rRNA gene fragments were amplified as an internal control while the rfbO157 and flicH7 gene PCR were used to confirm identities of isolates. STEC virulence genes stx1, stx2, eaeA and the hlyA were detected using PCR and the genetic relatedness of the isolates was determined using Pulse Field Gel electrophoresis (PFGE). A total of 69 (26.5%) E. coli O157:H7 isolates were detected in samples obtained from all the eight farms. A large proportions of the E. coli isolates possessed the stx1 (66.7%) and stx2 (97.1%) genes respectively. In addition, other accessory virulence genes eaeA and hlyA were detected in 30 (43.5%) and 43 (62.3%) of the E. coli isolates respectively. Pulsed-Filed Gel Electrophoresis (PFGE) analysis grouped these isolates into 6 clusters and the largest cluster contained 17 isolates originating from different farms. These results provide valid evidence that cattle harbour virulent and genetically similar E. coli strains particularly those belonging to the serotype O157 and therefore these animals may serve as possible source for zoonotic transfer of these pathogens to humans. The implication is that these isolates may have severe public health consequences on consumers.

Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue (AT) and could lead to renal failure in humans. However, the effect of Seipin on renal function is poorly understood. Here we report that Seipin knockout (SKO) mice exhibited impaired renal function, enlarged glomerular and mesangial surface areas, renal depositions of lipid, and advanced glycation end products. Elevated glycosuria and increased electrolyte excretion were also detected. Relative renal gene expression in fatty acid oxidation and reabsorption pathways were impaired in SKO mice. Elevated glycosuria might be associated with reduced renal glucose transporter 2 levels. To improve renal function, AT transplantation or leptin administration alone was performed. Both treatments effectively ameliorated renal injury by improving all of the parameters that were measured in the kidney. The treatments also rescued insulin resistance and low plasma leptin levels in SKO mice. Our findings demonstrate for the first time that Seipin deficiency induces renal injury, which is closely related to glucolipotoxicity and impaired renal reabsorption in SKO mice, and is primarily caused by the loss of AT and especially the lack of leptin. AT transplantation and leptin administration are two effective treatments for renal injury in Seipin-deficient mice.-Liu, X.-J., Wu, X.-Y., Wang, H., Wang, S.-X., Kong, W., Zhang, L., Liu, G., Huang, W. Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Light and electron microscopic studies of chronic renal failure using an adenine rat model

Objectives This work aimed to study chronic renal failure (CRF) in an adenine induced rat model using light microscopic, electron microscopic examinations in addition to morphometric studies. Past studies of adenine induced rat model of CRF did not emphasize on the electron microscopic changes that accompany CRF. Background Long term feeding of adenine to rats produced metabolic changes resembling chronic renal failure in humans. Among the changes happened were loss of weight and accumulation of uremic toxins (urea and creatinine). The pathological findings in the kidneys revealed glomerular and tubulo-interstitial damage. In the current work, we stressed on the changes that happen in the ultra-structural level. Methods Thirty adult male albino rats were divided into 2 groups: Group (I) ten rats, kept without any treatment, and sacrificed after 4 weeks. Group II (chronic renal failure induced group) twenty rats, received adenine powder daily (0.75% w/w for 4 weeks in food i.e., a daily adenine dose of 0.075 grams was added to 10 grams of food for each rat). Initial and final weights were recorded. Blood samples were collected for kidney function tests. Kidney sections were prepared for light and electron microscopic examination. Morphometric and statistical analysis were done. Results In comparison with the control group, the CRF induced group showed a significant decrease in their final body weight (P Conclusion Long term feeding of adenine exerted a marked inflammatory, fibrotic and apoptotic accelerating effect on both the glomeruli and the tubules.

The Kidney: An Organ in the Front Line of Oxidative Stress-Associated Pathologies.

Both acute kidney injury (AKI) and chronic kidney disease (CKD) are major causes of renal failure in humans and are associated with high incidences of morbidity and mortality rates. AKI and CKD are closely interconnected, and fueled by the obesity and diabetes epidemic, their prevalence is alarmingly increasing to the point that it currently represents a major heath issue worldwide. The kidney is an organ that is particularly sensitive to redox imbalance, resulting in excessive production of reactive oxygen species. Oxidative stress is viewed as a critical pathogenic factor implicated in the initiation, development, and progression of most renal diseases. This Forum discusses the redox-dependent factors and mechanisms accounting for the perturbation of renal function and circulation in the context of the major kidney pathologies linked to hypertension, diabetes, and cancer. Antioxid. Redox Signal. 25, 639-641.

Vitamin B12 Uptake by the Gut Commensal Bacteria Bacteroides thetaiotaomicron Limits the Production of Shiga Toxin by Enterohemorrhagic Escherichia coli.

Enterohemorrhagic Escherichia coli (EHEC) are foodborne pathogens responsible for the development of bloody diarrhea and renal failure in humans. Many environmental factors have been shown to regulate the production of Shiga toxin 2 (Stx2), the main virulence factor of EHEC. Among them, soluble factors produced by human gut microbiota and in particular, by the predominant species Bacteroides thetaiotaomicron (B. thetaiotaomicron), inhibit Stx2 gene expression. In this study, we investigated the molecular mechanisms underlying the B. thetaiotaomicron-dependent inhibition of Stx2 production by EHEC. We determined that Stx2-regulating molecules are resistant to heat treatment but do not correspond to propionate and acetate, two short-chain fatty acids produced by B. thetaiotaomicron. Moreover, screening of a B. thetaiotaomicron mutant library identified seven mutants that do not inhibit Stx2 synthesis by EHEC. One mutant has impaired production of BtuB, an outer membrane receptor for vitamin B12. Together with restoration of Stx2 level after vitamin B12 supplementation, these data highlight vitamin B12 as a molecule produced by gut microbiota that modulates production of a key virulence factor of EHEC and consequently may affect the outcome of an infection.

Effects of Drugs on Serum Biochemical Profile and Renal Failure in Humans and Experimental Rats: A Preliminary Report

Effects of Drugs on Serum Biochemical Profile and Renal Failure in Humans and Experimental Rats: A Preliminary Report

Endothelial Progenitor Cells Derived From Wharton's Jelly of Human Umbilical Cord Attenuate Ischemic Acute Kidney Injury by Increasing Vascularization and Decreasing Apoptosis, Inflammation, and Fibrosis.

Ischemia-reperfusion (I/R) injury to the kidney, a major cause of acute renal failure in humans, is associated with a high mortality, and the development of a new therapeutic strategy is therefore highly desirable. In this study, we examined the therapeutic potential of implantation of endothelial progenitor cells (EPCs) isolated from Wharton's jelly of human umbilical cords in the treatment of renal I/R injury in mice. To visualize the localization of the transplanted EPCs, the cells were labeled with Q-tracker before injection into the renal capsule. Mice with renal I/R injury showed a significant increase in blood urea nitrogen and creatinine levels, and these effects were decreased by EPC transplantation. The kidney injury score in the mice with I/R injury was also significantly decreased by EPC transplantation. EPC transplantation increased the microvascular density, and some of the EPCs surrounded and were incorporated into microvessels. In addition, EPC transplantation inhibited the I/R-induced cell apoptosis of endothelial, glomerular, and renal tubular cells, as demonstrated by TUNEL staining, and significantly reduced reactive oxygen species production and the expression of the inflammatory chemokines macrophage inflammatory protein-2 and keratinocyte-derived cytokine, as shown by immunostaining and ELISA. Moreover, EPC transplantation reduced I/R-induced fibrosis, as demonstrated by immunostaining for S100A4, a fibroblast marker, and by Jones silver staining. To our knowledge, this is the first report that transplantation of EPCs from Wharton's jelly of human umbilical cords might provide a novel therapy for ischemic acute kidney injury by promoting angiogenesis and inhibiting apoptosis, inflammation, and fibrosis.

PS-240 Developing A Toxic Paediatric Animal Model Of Non-oliguric Acute Renal Injury With Cisplatin: Abstract PS-240 Table 1

Introduction Developing a non-oliguric paediatric animal model of acuterenal injury (AKI) could be useful to study the evolution of diuresis after treatments. Cisplatin causes a dose-dependant poliuric renal failure in humans. A dose of 5 mg/kg has been used in rats to produced AKI but there are no studies in pigs. Objectives To define the target dose of Cisplatin that develops anon-oliguric toxic acute kidney injury in piglets. Methods A prospective experimental study was performed in 8 piglets (mean 10 kg). Three different intravenous doses of Cisplatin (2, 3 and5 mg/kg) and two different periods of time between administration and evaluation (2 and 4 days) were studied. Urine and blood samples were collected. Results Results are presented in Table 1. A dose of 2 mg/kg did not produce important alteration of renal function at any given time. A very severe oliguric AKI with extremely high hyperkalemia was observed four days after a 3 mg/kg dose and 3 days after a 5 mg/kd dose. A dose of 3 mg/kg administrated 48 h before produced an important AKI without severe hyperkalemia. Conclusions A dose of 3 mg/kgof intravenous cisplatin producednon-oliguric AKI after 48 h in piglets. This dose and interval can be used for toxic paediatric animal models of AKI.

Strain-Dependent Cellular Immune Responses in Cattle following Escherichia coli O157:H7 Colonization

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic diarrhea and potentially fatal renal failure in humans. Ruminants are considered to be the primary reservoir for human infection. Vaccines that reduce shedding in cattle are only partially protective, and their underlying protective mechanisms are unknown. Studies investigating the response of cattle to colonization generally focus on humoral immunity, leaving the role of cellular immunity unclear. To inform future vaccine development, we studied the cellular immune responses of cattle during EHEC O157:H7 colonization. Calves were challenged either with a phage type 21/28 (PT21/28) strain possessing the Shiga toxin 2a (Stx2a) and Stx2c genes or with a PT32 strain possessing the Stx2c gene only. T-helper cell-associated transcripts at the terminal rectum were analyzed by reverse transcription-quantitative PCR (RT-qPCR). Induction of gamma interferon (IFN-γ) and T-bet was observed with peak expression of both genes at 7 days in PT32-challenged calves, while upregulation was delayed, peaking at 21 days, in PT21/28-challenged calves. Cells isolated from gastrointestinal lymph nodes demonstrated antigen-specific proliferation and IFN-γ release in response to type III secreted proteins (T3SPs); however, responsiveness was suppressed in cells isolated from PT32-challenged calves. Lymph node cells showed increased expression of the proliferation marker Ki67 in CD4(+) T cells from PT21/28-challenged calves, NK cells from PT32-challenged calves, and CD8(+) and γδ T cells from both PT21/28- and PT32-challenged calves following ex vivo restimulation with T3SPs. This study demonstrates that cattle mount cellular immune responses during colonization with EHEC O157:H7, the temporality of which is strain dependent, with further evidence of strain-specific immunomodulation.

Characterization of the SAM domain of the PKD-related protein ANKS6 and its interaction with ANKS3.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to end-stage renal failure in humans. In the PKD/Mhm(cy/+) rat model of ADPKD, the point mutation R823W in the sterile alpha motif (SAM) domain of the protein ANKS6 is responsible for disease. SAM domains are known protein-protein interaction domains, capable of binding each other to form polymers and heterodimers. Despite its physiological importance, little is known about the function of ANKS6 and how the R823W point mutation leads to PKD. Recent work has revealed that ANKS6 interacts with a related protein called ANKS3. Both ANKS6 and ANKS3 have a similar domain structure, with ankyrin repeats at the N-terminus and a SAM domain at the C-terminus.ResultsThe SAM domain of ANKS3 is identified as a direct binding partner of the ANKS6 SAM domain. We find that ANKS3-SAM polymerizes and ANKS6-SAM can bind to one end of the polymer. We present crystal structures of both the ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex, revealing the molecular details of their association. We also learn how the R823W mutation disrupts ANKS6 function by dramatically destabilizing the SAM domain such that the interaction with ANKS3-SAM is lost.ConclusionsANKS3 is a direct interacting partner of ANKS6. By structurally and biochemically characterizing the interaction between the ANKS3 and ANKS6 SAM domains, our work provides a basis for future investigation of how the interaction between these proteins mediates kidney function.