Resveratrol Improves Hyperuricemia and Ameliorates Renal Injury by Modulating the Gut Microbiota.

Resveratrol (RES) has been reported to prevent hyperuricemia (HUA); however, its effect on intestinal uric acid metabolism remains unclear. This study evaluated the impact of RES on intestinal uric acid metabolism in mice with HUA induced by a high-fat diet (HFD). Moreover, we revealed the underlying mechanism through metagenomics, fecal microbiota transplantation (FMT), and 16S ribosomal RNA analysis. We demonstrated that RES reduced the serum uric acid, creatinine, urea nitrogen, and urinary protein levels, and improved the glomerular atrophy, unclear renal tubule structure, fibrosis, and renal inflammation. The results also showed that RES increased intestinal uric acid degradation. RES significantly changed the intestinal flora composition of HFD-fed mice by enriching the beneficial bacteria that degrade uric acid, reducing harmful bacteria that promote inflammation, and improving microbial function via the upregulation of purine metabolism. The FMT results further showed that the intestinal microbiota is essential for the effect of RES on HUA, and that Lactobacillus may play a key role in this process. The present study demonstrated that RES alleviates HFD-induced HUA and renal injury by regulating the gut microbiota composition and the metabolism of uric acid.

Deep-learning model for evaluating histopathology of acute renal tubular injury.

Tubular injury is the most common cause of acute kidney injury. Histopathological diagnosis may help distinguish between the different types of acute kidney injury and aid in treatment. To date, a limited number of study has used deep-learning models to assist in the histopathological diagnosis of acute kidney injury. This study aimed to perform histopathological segmentation to identify the four structures of acute renal tubular injury using deep-learning models. A segmentation model was used to classify tubule-specific injuries following cisplatin treatment. A total of 45 whole-slide images with 400 generated patches were used in the segmentation model, and 27,478 annotations were created for four classes: glomerulus, healthy tubules, necrotic tubules, and tubules with casts. A segmentation model was developed using the DeepLabV3 architecture with a MobileNetv3-Large backbone to accurately identify the four histopathological structures associated with acute renal tubular injury in PAS-stained mouse samples. In the segmentation model for four structures, the highest Intersection over Union and the Dice coefficient were obtained for the segmentation of the "glomerulus" class, followed by "necrotic tubules," "healthy tubules," and "tubules with cast" classes. The overall performance of the segmentation algorithm for all classes in the test set included an Intersection over Union of 0.7968 and a Dice coefficient of 0.8772. The Dice scores for the glomerulus, healthy tubules, necrotic tubules, and tubules with cast are 91.78 ± 11.09, 87.37 ± 4.02, 88.08 ± 6.83, and 83.64 ± 20.39%, respectively. The utilization of deep learning in a predictive model has demonstrated promising performance in accurately identifying the degree of injured renal tubules. These results may provide new opportunities for the application of the proposed methods to evaluate renal pathology more effectively.

Tubular CPT1A deletion minimally affects aging and chronic kidney injury.

Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO mice had a modest decrease in palmitate oxidation but retained the ability to metabolize long-chain fatty acids. Very-long-chain fatty acids, exclusively oxidized by peroxisomes, were reduced in kidneys lacking tubular CPT1A, consistent with increased peroxisomal activity. Single-nuclear RNA-Seq showed significantly increased expression of peroxisomal FAO enzymes in proximal tubules of mice lacking tubular CPT1A. These data suggest that peroxisomal FAO may compensate in the absence of CPT1A, and future genetic studies are needed to confirm the role of peroxisomal ß-oxidation when mitochondrial FAO is impaired.

MicroRNA-5010-5p ameliorates high-glucose induced inflammation in renal tubular epithelial cells by modulating the expression of PPP2R2D.

INTRODUCTION: We previously reported the significant upregulation of eight circulating exosomal microRNAs (miRNAs) in patients with diabetic kidney disease (DKD). However, their specific roles and molecular mechanisms in the kidney remain unknown. Among the eight miRNAs, we evaluated the effects of miR-5010-5p on renal tubular epithelial cells under diabetic conditions in this study. RESEARCH DESIGN AND METHODS: We transfected the renal tubular epithelial cell line, HK-2, with an miR-5010-5p mimic using recombinant plasmids. The target gene of hsa-miR-5010-5p was identified using a dual-luciferase assay. Cell viability was assessed via the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Moreover, mRNA and protein expression levels were determined via real-time PCR and western blotting, respectively. RESULTS: High glucose levels did not significantly affect the intracellular expression of miR-5010-5p in HK-2 cells. Transfection of the miR-5010-5p mimic caused no change in cell viability. However, miR-5010-5p-transfected HK-2 cells exhibited significantly decreased expression levels of inflammatory cytokines, such as the monocyte chemoattractant protein-1, interleukin-1ß, and tumor necrosis factor-ɑ, under high-glucose conditions. These changes were accompanied by the restored expression of phosphorylated AMP-activated protein kinase (AMPK) and decreased phosphorylation of nuclear factor-kappa B. Dual-luciferase assay revealed that miR-5010-5p targeted the gene, protein phosphatase 2 regulatory subunit B delta (PPP2R2D), a subunit of protein phosphatase 2A, which modulates AMPK phosphorylation. CONCLUSIONS: Our findings suggest that increased miR-5010-5p expression reduces high glucose-induced inflammatory responses in renal tubular epithelial cells via the regulation of the target gene, PPP2R2D, which modulates AMPK phosphorylation. Therefore, miR-5010-5p may be a promising therapeutic target for DKD.

Investigation of the Relationship of Nesfatin-1, Adropin Levels and Claudin-2, Renalase Immunoreactivity with Kidney Function in an Experimental Hypertension Model.

OBJECTIVE: Hypertension is one of the cardiovascular diseases that causes the most mortality, and 95% of the causes are unknown. The aim of the study was to examine the possible correlation of nesfatin-1 levels, adropin levels, claudin-2 immunoreactivity (claudin-2 expression in the renal proximal tubule), and renalase immunoreactivity (renalase expression in the renal proximal tubule) with arterial blood pressure, kidney function, and kidney damage. METHODS: Adult male Sprague Dawley rats were divided into control and hypertension groups (8 per group). Angiotensin II vehicle was given to the control group and angiotensin II (0.7 mg/kg/day) to the hypertension group, both via an osmotic mini pump for 7 days. The animals blood pressures were measured by tail cuff plethysmography on days 1, 3, 5, and 7. On day 7, 24-hour urine, blood, and tissues were collected from the rats. RESULTS: In the hypertension group compared with the control group, there was an increase in systolic blood pressure levels after day 1. While claudin-2 immunoreactivity was reduced in the kidneys, renalase immunoreactivity was increased. There was a decrease in creatinine clearance and an increase in fractional potassium excretion (P < .05). CONCLUSION: Our results showed that claudin-2 and renalase are associated with renal glomerular and tubular dysfunction and may play discrete roles in the pathogenesis of hypertension. We believe that these potential roles warrant further investigation.

Ferroptosis-related genes, a novel therapeutic target for focal segmental glomerulosclerosis.

Recent studies have suggested that ferroptosis participates in various renal diseases. However, its effect on focal segmental glomerulosclerosis remains unclear. This study analyzed the GSE125779 and GSE121211 datasets to identify the differentially expressed genes (DEGs) in renal tubular samples with and without FSGS. The Cytoscape was used to construct the protein-protein interaction network. Moreover, the ferroptosis-related genes (FRGs) were obtained from the ferroptosis database, while ferroptosis-related DEGs were obtained by intersection with DEGs. The target genes were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The GSE108112 dataset was used to verify the expression of target FRGs. Besides, we built the mRNA-miRNA network regarding FRGs using the NetworkAnalyst database, and circRNAs corresponding to key miRNAs were predicted in the ENCORI database. In this study, 16 ferroptosis-related DEGs were identified between FSGS and healthy subjects, while five co-expressed genes were obtained by three topological algorithms in Cytoscape. These included the most concerned Hub genes JUN, HIF1A, ALB, DUSP1 and ATF3. The KEGG enrichment analysis indicated that FRGs were associated with mitophagy, renal cell carcinoma, and metabolic pathways. Simultaneously, the co-expressed hub genes were analyzed to construct the mRNA-miRNA interaction network and important miRNAs such as hsa-mir-155-5p, hsa-mir-1-3p, and hsa-mir-124-3p were obtained. Finally, 75 drugs targeting 54 important circRNAs and FRGs were predicted. This study identified the Hub FRGs and transcriptomic molecules from FSGS in renal tubules, thus providing novel diagnostic and therapeutic targets for FSGS.

Renal diseases that course with hypomagnesemia. Comments on a new hereditary hypomagnesemic tubulopathy.

Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described.

Comparison of preparation methods of rat kidney single-cell suspensions.

Preparation of kidney tissue single-cell suspensions is the basis of single-cell sequencing, flow cytometry and primary cell culture, but it is difficult to prepare high quality whole kidney single-cell suspensions because of the complex structure of the kidney. We explored a technique called stepwise enzymatic digestion (StE) method for preparing a single-cell suspension of rat whole kidney tissue which contained three main steps. The first step is to cut the kidney into a homogenate. The second step is the digestion of renal tubules using Multi Tissue Dissociation Kit 2 and the last step is the digestion of glomeruli using type IV collagenase. We also compared it with two previous techniques, mechanical grinding method and simple enzymatic digestion method. The StE method had the advantages of high intrinsic glomerular cells and immune cells harvest rate, high singlets rate and high cell viability compared with the other two techniques. In conclusion, the StE method is feasible, highly efficient, and worthy of further research and development.

AI models for automated segmentation of engineered polycystic kidney tubules.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic, rare disease, characterized by the formation of multiple cysts that grow out of the renal tubules. Despite intensive attempts to develop new drugs or repurpose existing ones, there is currently no definitive cure for ADPKD. This is primarily due to the complex and variable pathogenesis of the disease and the lack of models that can faithfully reproduce the human phenotype. Therefore, the development of models that allow automated detection of cysts' growth directly on human kidney tissue is a crucial step in the search for efficient therapeutic solutions. Artificial Intelligence methods, and deep learning algorithms in particular, can provide powerful and effective solutions to such tasks, and indeed various architectures have been proposed in the literature in recent years. Here, we comparatively review state-of-the-art deep learning segmentation models, using as a testbed a set of sequential RGB immunofluorescence images from 4 in vitro experiments with 32 engineered polycystic kidney tubules. To gain a deeper understanding of the detection process, we implemented both pixel-wise and cyst-wise performance metrics to evaluate the algorithms. Overall, two models stand out as the best performing, namely UNet++ and UACANet: the latter uses a self-attention mechanism introducing some explainability aspects that can be further exploited in future developments, thus making it the most promising algorithm to build upon towards a more refined cyst-detection platform. UACANet model achieves a cyst-wise Intersection over Union of 0.83, 0.91 for Recall, and 0.92 for Precision when applied to detect large-size cysts. On all-size cysts, UACANet averages at 0.624 pixel-wise Intersection over Union. The code to reproduce all results is freely available in a public GitHub repository.

The Ip6k1 and Ip6k2 Kinases Are Critical for Normal Renal Tubular Function.

SIGNIFICANCE STATEMENT: Kidneys are gatekeepers of systemic inorganic phosphate balance because they control urinary phosphate excretion. In yeast and plants, inositol hexakisphosphate kinases (IP6Ks) are central to regulate phosphate metabolism, whereas their role in mammalian phosphate homeostasis is mostly unknown. We demonstrate in a renal cell line and in mice that Ip6k1 and Ip6k2 are critical for normal expression and function of the major renal Na + /Pi transporters NaPi-IIa and NaPi-IIc. Moreover, Ip6k1/2-/- mice also show symptoms of more generalized kidney dysfunction. Thus, our results suggest that IP6Ks are essential for phosphate metabolism and proper kidney function in mammals. BACKGROUND: Inorganic phosphate is an essential mineral, and its plasma levels are tightly regulated. In mammals, kidneys are critical for maintaining phosphate homeostasis through mechanisms that ultimately regulate the expression of the Na + /Pi cotransporters NaPi-IIa and NaPi-IIc in proximal tubules. Inositol pyrophosphate 5-IP 7 , generated by IP6Ks, is a main regulator of phosphate metabolism in yeast and plants. IP6Ks are conserved in mammals, but their role in phosphate metabolism in vivo remains unexplored. METHODS: We used in vitro (opossum kidney cells) and in vivo (renal tubular-specific Ip6k1/2-/- mice) models to analyze the role of IP6K1/2 in phosphate homeostasis in mammals. RESULTS: In both systems, Ip6k1 and Ip6k2 are responsible for synthesis of 5-IP 7 . Depletion of Ip6k1/2 in vitro reduced phosphate transport and mRNA expression of Na + /Pi cotransporters, and it blunts phosphate transport adaptation to changes in ambient phosphate. Renal ablation of both kinases in mice also downregulates the expression of NaPi-IIa and NaPi-IIc and lowered the uptake of phosphate into proximal renal brush border membranes. In addition, the absence of Ip6k1 and Ip6k2 reduced the plasma concentration of fibroblast growth factor 23 and increased bone resorption, despite of which homozygous males develop hypophosphatemia. Ip6k1/2-/- mice also show increased diuresis, albuminuria, and hypercalciuria, although the morphology of glomeruli and proximal brush border membrane seemed unaffected. CONCLUSIONS: Depletion of renal Ip6k1/2 in mice not only altered phosphate homeostasis but also dysregulated other kidney functions.

In vivo monitoring of renal tubule volume fraction using dynamic parametric MRI.

PURPOSE: The increasing incidence of kidney diseases is a global concern, and current biomarkers and treatments are inadequate. Changes in renal tubule luminal volume fraction (TVF) serve as a rapid biomarker for kidney disease and improve understanding of renal (patho)physiology. This study uses the amplitude of the long T2 component as a surrogate for TVF in rats, by applying multiexponential analysis of the T2-driven signal decay to examine micromorphological changes in renal tissue. METHODS: Simulations were conducted to identify a low mean absolute error (MAE) protocol and an accelerated protocol customized for the in vivo study of T2 mapping of the rat kidney at 9.4 T. We then validated our bi-exponential approach in a phantom mimicking the relaxation properties of renal tissue. This was followed by a proof-of-principle demonstration using in vivo data obtained during a transient increase of renal pelvis and tubular pressure. RESULTS: Using the low MAE protocol, our approach achieved an accuracy of MAE < 1% on the mechanical phantom. The T2 mapping protocol customized for in vivo study achieved an accuracy of MAE < 3%. Transiently increasing pressure in the renal pelvis and tubules led to significant changes in TVF in renal compartments: ΔTVFcortex = 4.9%, ΔTVFouter_medulla = 4.5%, and ΔTVFinner_medulla = -14.6%. CONCLUSION: These results demonstrate that our approach is promising for research into quantitative assessment of renal TVF in in vivo applications. Ultimately, these investigations have the potential to help reveal mechanism in acute renal injury that may lead to chronic kidney disease, which will support research into renal disorders.

Single-cell sequencing dissects the transcriptional identity of activated fibroblasts and identifies novel persistent distal tubular injury patterns in kidney fibrosis.

Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic kidney disease (CKD). Persistent fibroblast activation and tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular and transcriptional landscapes of CKD and specific activated kidney fibroblast clusters remain elusive. Here, we analyzed single cell transcriptomic profiles of two clinically relevant kidney fibrosis models which induced robust kidney parenchymal remodeling. We dissected the molecular and cellular landscapes of kidney stroma and newly identified three distinctive fibroblast clusters with "secretory", "contractile" and "vascular" transcriptional enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline of mature epithelial markers and elevation of stromal and injury markers. Notably, frTECs shared transcriptional identity with distal nephron segments of the embryonic kidney. Moreover, we identified that both models exhibited robust and previously unrecognized distal spatial pattern of TEC injury, outlined by persistent elevation of renal TEC injury markers including Krt8 and Vcam1, while the surviving proximal tubules (PTs) showed restored transcriptional signature. We also found that long-term kidney injuries activated a prominent nephrogenic signature, including Sox4 and Hox gene elevation, which prevailed in the distal tubular segments. Our findings might advance understanding of and targeted intervention in fibrotic kidney disease.

Assessment of osteopontin as an early nephrotoxicity indicator in human renal proximal tubule cells and its application in evaluating lanthanum-induced nephrotoxicity.

Nephrotoxicity is a common adverse effect induced by various chemicals, necessitating the development of reliable toxicity screening models for nephrotoxicity assessment. In this study, we assessed a group of nephrotoxicity indicators derived from different toxicity pathways, including conventional endpoints and kidney tubular injury biomarkers such as clusterin (CLU), kidney injury molecule-I (KIM-1), osteopontin (OPN), and neutrophil gelatinase-associated lipocalin (NGAL), using HK-2 and induced pluripotent stem cells (iPSCs)-derived renal proximal tubular epithelial-like cells (PTLs). Among the biomarkers tested, OPN emerged as the most discerning and precise marker. The predictive potential of OPN was tested using a panel of 10 nephrotoxic and 5 non-nephrotoxic compounds. The results demonstrated that combining OPN with the half-maximal inhibitory concentration (IC50) enhanced the diagnostic accuracy in both cellular models. Additionally, PTLs cells showed superior predictive efficacy for nephrotoxicity compared to HK-2 cells in this investigation. The two cellular models were utilized to evaluate the nephrotoxicity of lanthanum. The findings indicated that lanthanum possesses nephrotoxic properties; however, the degree of nephrotoxicity was relatively low, consistent with the outcomes of in vivo experiments.

Corin protects against acute kidney injury in mice through anti-inflammatory effects.

Corin is a type II transmembrane serine protease mainly expressed in the heart. Recently, corin was detected in the kidney and was reported to be associated with multiple kidney diseases. To date, its effect on acute kidney injury (AKI) has not been clarified. Here, we found that corin was constitutively expressed in renal tubules, especially in proximal and distal tubular epithelial cells. The expression of corin was dramatically reduced in ischemia/reperfusion injury (IRI)-induced AKI mouse model and oxygen-glucose deprivation (OGD)-induced human proximal tubular epithelial (HK-2) cells injury model, suggesting a potential role of corin in AKI. Corin deficient mice exhibited aggravated renal injury in AKI, as indicated by higher elevation of serum creatinine (SCr) and blood urea nitrogen (BUN), more severe tubular damage, and increased cell death versus wild type mice, demonstrating a protective effect of corin on AKI. In vitro overexpression of corin didn't directly alleviate hypoxia-induced HK-2 cells death, revealing that the protective effect of corin against AKI is not due to direct protection of tubular epithelial cells but may be through indirect protection. Microarray analysis showed enhanced inflammatory chemokines signaling and leukocyte chemotaxis in corin-/- mice after AKI, identifying an important role of corin in halting leukocyte chemotaxis and inflammatory response. Consistently, corin-/- mice after AKI displayed increased tubulointerstitial neutrophils and macrophages infiltration, as well as higher inflammatory mediators in kidneys. Taken together, our study indicates that tubular corin exerts a protective effect against AKI through negative regulation of chemotaxis signaling and inflammation in the kidney.

IGF2BP3-stabilized CAMK1 regulates the mitochondrial dynamics of renal tubule to alleviate diabetic nephropathy.

BACKGROUND: CAMK1 has been shown to be involved in human disease progression via regulating mitochondrial dynamics. However, whether CAMK1 mediates mitochondrial dynamics to regulate diabetic nephropathy (DN) process remains unclear. METHODS: Mice were injected with streptozotocin (STZ) to mimic diabetic mice models in vivo, and mice with proximal tubule-specific knockout of CAMK1 (CAMK1-KO) were generated. HK-2 cells were treated with high-glucose (HG) to mimic DN cell model in vitro. Histopathological analysis was performed to confirm kidney injury in mice. ROS production and apoptosis were assessed by DHE staining and TUNEL staining. Mitochondria morphology was observed and analyzed by electron microscopy. Mitochondrial membrane potential was detected by JC-1 staining, and cell proliferation was measured by EdU assay. The mRNA and protein expression were examined by qRT-PCR, western blot and immunostaining. RNA interaction was confirmed by RIP assay and dual-luciferase reporter assay. The mRNA stability was tested by actinomycin D treatment, and m6A level was examined by MeRIP assay. RESULTS: CAMK1 was reduced in DN patients and STZ-induced diabetic mice. Conditional deletion of CAMK1 aggravated kidney injury and promoted mitochondrial fission in diabetic mice. CAMK1 overexpression inhibited mitochondrial fission to alleviate HG-induced HK-2 cell apoptosis. IGF2BP3 promoted the stability of CAMK1 mRNA by m6A modification. IGF2BP3 inhibited mitochondrial fission to repress cell apoptosis in vitro and kidney injury in vivo by increasing CAMK1 expression. CONCLUSION: IGF2BP3-mediated CAMK1 mRNA stability alleviated DN progression by inhibiting mitochondria fission.

Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na+ Channel (ENaC).

BACKGROUND: Kir4.2 and Kir4.1 play a role in regulating membrane transport in the proximal tubule (PT) and in the distal-convoluted-tubule (DCT), respectively. METHODS: We generated kidney-tubule-specific-AT1aR-knockout (Ks-AT1aR-KO) mice to examine whether renal AT1aR regulates Kir4.2 and Kir4.1. RESULTS: Ks-AT1aR-KO mice had a lower systolic blood pressure than Agtr1aflox/flox (control) mice. Ks-AT1aR-KO mice had a lower expression of NHE3 (Na+/H+-exchanger 3) and Kir4.2, a major Kir-channel in PT, than Agtr1aflox/flox mice. Whole-cell recording also demonstrated that the membrane potential in PT of Ks-AT1aR-KO mice was lesser negative than Agtr1aflox/flox mice. The expression of Kir4.1 and Kir5.1, Kir4.1/Kir5.1-mediated K+ currents of DCT and DCT membrane potential in Ks-AT1aR-KO mice, were similar to Agtr1aflox/flox mice. However, angiotensin II perfusion for 7 days hyperpolarized the membrane potential in PT and DCT of the control mice but not in Ks-AT1aR-KO mice, while angiotensin II perfusion did not change the expression of Kir4.1, Kir4.2, and Kir5.1. Deletion of AT1aR did not significantly affect the expression of αENaC (epithelial Na+ channel) and ßENaC but increased cleaved γENaC expression. Patch-clamp experiments demonstrated that deletion of AT1aR increased amiloride-sensitive Na+-currents in the cortical-collecting duct but not in late-DCT. However, tertiapin-Q sensitive renal outer medullary potassium channel currents were similar in both genotypes. CONCLUSIONS: AT1aR determines the baseline membrane potential of PT by controlling Kir4.2 expression/activity but AT1aR is not required for determining the baseline membrane potential of the DCT and Kir4.1/Kir5.1 activity/expression. However, AT1aR is required for angiotensin II-induced hyperpolarization of basolateral membrane of PT and DCT. Deletion of AT1aR had no effect on baseline renal outer medullary potassium channel activity but increased ENaC activity in the CCD.

Mitochondrial Dysfunction in Kidney Tubulopathies.

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.