Renal Structural Changes Research Articles

Phenylethanol Glycosides from Cistanche tubulosa Modulate the Gut Microbiota and Cecal Metabolites to Ameliorate Diabetic Nephropathy Induced by Streptozotocin Combined with High-Fat Diet in Rats.

Diabetic nephropathy (DN) is a prevalent complication and serious microvascular of diabetes mellitus. After previous studies, we found that phenylethanol glycosides (CPhGs) derived from Cistanche tubulosa (Schenk) Wight exerts antidiabetic and renoprotective effects. However, the effects of CPhGs on DN remain incompletely understood. The study aimed to examine the effects of CPhGs on DN in rats and explore the underlying mechanism involved. A DN rat model was established by streptozotocin (STZ) combined with a high-fat diet. Reagent kits were used to assess the extent to which CPhGs ameliorate hyperglycemia, insulin resistance (IR), renal dysfunction, kidney oxidative stress, and peripheral inflammation. Histology and immunohistochemical staining were used to detect the changes in renal tissue structure and the expression levels of α-smooth muscle actin (α-SMA) and collagen I. Furthermore, we analyzed the cecal contents of DN rats to investigate the effect of CPhGs on gut microbiota by using 16S rRNA sequencing and broad-spectrum metabolite profiling. The results showed that CPhGs demonstrated a range of advantageous outcomes in DN, encompassing the enhancement of kidney function and alleviation of hyperglycemia, IR, renal injury, oxidative stress, and peripheral inflammatory reactions. In addition, CPhGs regulated the abundance of the [Eubacterium]_coprostanoligenes_group, Oscillospiraceae_UCG-005, etc. to modulate the gut microbiota. CPhGs significantly upregulated the content of vitamin B6 and tyrosyl-tryptophan and downregulated histamine, L-methionine, etc. In summary, the therapeutic efficacy of CPhGs on DN rats may be achieved by modulating the gut microbiota and cecal metabolites to restore the metabolic disorders of vitamin B6, histidine, etc.

Renal structural changes and apelin receptor expression in spontaneously hypertensive rats: implications for hypertension-induced kidney injury.

Arterial hypertension is a primary risk factor for kidney disease. Recent advances have implied a potential link between the apelin system and renal homeostasis. We used 6- and 12-month-old spontaneously hypertensive rats and age-matched normotensive controls to assess the changes in the renal expression of the apelin receptor by immunohistochemical method. The study also evaluated correlations between the renal apelin receptor's expression and renal injury indicators. The histological analysis showed elevated glomerular sclerosis and tubulointerstitial damage indices in both groups of hypertensive rats compared to age-matched controls. Older rats within each group exhibited higher scores than younger ones. The immunohistochemical analysis revealed varying apelin receptor expression patterns, with tubular expression intensifying both with hypertension severity and age. Glomerular expression was notably higher in older hypertensive rats compared to normotensive controls. We reported significant positive correlations between glomerular apelin receptor expression and glomerular sclerosis index in older hypertensive animals. Similarly, a positive correlation between tubular apelin receptor expression and tubulointerstitial damage index was discovered in hypertensive rats, suggesting hypertension-related changes in apelin receptor expression and renal damage. Our study found kidney changes and varying apelin receptor correlations in hypertensive rat kidneys, suggesting complex roles needing research.

#2614 Extramedullary hematopoiesis resembling an asymptomatic renal mass: an unusual presentation

Abstract Background and Aims Extramedullary hematopoiesis (EMH) is the body's compensatory response to deficient erythropoiesis by the bone marrow or accelerated destruction of erythrocytes. The term refers to deposits of erythroid precursors in organs outside the bone marrow, most frequently occurring in the liver, spleen and lymph nodes. We report a case of perirenal EMH revealed by ultrasound (US) integrated with magnetic resonance imaging (MRI) in a patient with primary myelofibrosis. This case reveals the importance of point-of-care US (POCUS) to complete the nephrological examination and better direct the diagnostic process. Method A 68 yo man with a myeloproliferative disease was referred to nephrologists due to the discovery of altered creatinine and urea values in the blood tests (1.6 and 65 mg/dl, respectively, eGFR 43 ml/min EPI-CKD), reduction of hemoglobin value (6,4 g/dl) despite erythropoietin (EPO) and iron supplements, and for renal cysts follow-up. The standard urinalysis showed no abnormalities and negative fecal occult blood tests. Physical examination and US were performed during outpatient visit. Results On US abdominal evaluation, an already known severe splenic enlargement was found (LD 18 cm, Fig. 2), with the presence of two peri centimetric accessory spleens at the hilum. In the prone position, a bilobed, isoechoic structure was noticed emerging from the posterior profile of the upper pole of the left kidney: it measured 3.7 cm and didn't show a clear solution of continuity with the renal parenchyma. The color evaluation did not reveal hypervascularization. The uncertain nature of the lesion led us to perform an MRI, which showed bilaterally, along the posterior capsular margin, an isointense tissue thickening on T1 and slightly hyperintense and inhomogeneous on T2 with signs of diffusivity restriction, compatible in the first hypothesis with perirenal EMH (Fig. 1).These findings were absent in the annual US performed in hematology; they entered into the differential diagnosis with cysts or renal lesions. US first and then MRI made it possible to diagnose EMH and clinically justify the anemia and the low recent response to EPO. Conclusion Primary myelofibrosis is characterized by bone marrow fibrosis and the proliferation of megakaryocytes and granulocytes in the bone marrow and may result in progressive pancytopenia and EMH. Foci of EMH may develop or enlarge significantly after splenectomy, perhaps due to the loss of filtering function of the spleen. The kidney is an unusual site for EMH and it can be asymptomatic clinically. There have been few previous reports of EMH renal involvement, that can be parenchymal, intrapelvic or perirenal. In our patient, EMH diagnosis was coincidental but allowed us to place differential diagnosis with other diseases such as tumors, lymphomas, lipomatosis, renal inflammatory or infectious tissue, which generally present as a perirenal or parapelvic mass of uncertain etiology. In this case, POCUS allowed us to locate the mass and characterize it, excluding obstructive renal failure, and to establish a differential diagnosis with complex cysts or lymph node packages or others. Despite the reduced eGFR, renal function was stable in the previous and following months. According to the literature, we decided to perform only radiological exams because of the kidney biopsy risk of significant bleeding. In patients with hematologic disorders, it is important to investigate the presence of renal structural changes that require radiological follow-up and that could affect long-term prognosis.

FINERENONE TREATMENT PREVENTS GLOMERULAR DAMAGE AND RENAL INTERSTITIAL INFLAMMATION IN TYPE 1 DIABETIC RATS WITH CHRONIC KIDNEY DISEASE

Objective: Finerenone (FIN), a non-steroidal mineralocorticoid receptor antagonist, has shown a protective effect on kidney and cardiovascular damage progression in type 1 diabetic Munich Wistar Frömter rats with established chronic kidney disease (CKD). The gradual decline in kidney function in diabetic CKD is due to a thickening of glomerular and Bowman capsule basement membranes, mesangial matrix expansion, and tubulointerstitial fibrosis. In this study we aimed to characterize whether the renal protection of FIN is related to a decrease in kidney damage through histomorphological changes in diabetic MWF rats. Design and method: Diabetes was induced by a streptozotocin injection (15 mg/Kg, i.p.) together with exposure to a high fat/high sucrose (HF/HS) diet (MWF-D) for 6 weeks. The MWF-D-FIN group was additionally treated with 10 mg/Kg/day of FIN included in the HF/HS diet (n = 6/group). Morphometrical analysis of renal structural changes was performed under hematoxylin and eosin staining, and light microscopy. Matrix metalloproteinases (MMP)-2 and MMP-9 activities were determined by zymography. Results: MWF-D and MWF-D-EP rats exhibited significantly elevated glycemia, water intake, urine volume, glucosuria, and kidney weight compared to control MWF. Histological examination of kidney samples of MWF and MWF-D rats showed hypertrophic glomeruli with an increase of the glomerular tuft and the Bowman's space. These pathological alterations were prevented by FIN treatment. The percentage of glomerulosclerosis was significantly higher in MWF and MWF-D rats and 59% lower in the MWF-D-FIN group (p<0.001) whereas the glomerulosclerosis index was reduced to 33% by FIN (p<0.001). Moreover, MWF-D rats showed an increased interstitial inflammation index compared to MWF rats (p<0.001) which was reduced to 44% (p<0.001) in the MWF-D-FIN group. Since an increase in MMP-2 and MMP-9 activities are associated with fibrosis development, these were determined by zymography in kidney samples of all groups. Both MMP-2 and MMP-9 were significantly higher in MWF-D compared to MWF and decreased by FIN treatment. Conclusions: In conclusion FIN prevents the development of diabetic kidney damage due to a reduction in glomerular alterations and interstitial inflammation associated to an inhibition of MMP-2 and MMP-9 activities.

Co-exposure of arsenic and polystyrene-nanoplastics induced kidney injury by disrupting mitochondrial homeostasis and mtROS-mediated ferritinophagy and ferroptosis

Arsenic (As) and polystyrene nanoplastics (PSNPs) co-exposure induced biotoxicity and ecological risks have attracted wide attention. However, the combined effects of As and PSNPs on the kidney and their underlying mechanisms of toxicities remain to be explored. Here, we investigated the effects of As and PSNPs co-exposure on structure and function in mice kidney, and further explored the possible mechanisms. In this study, we identified that co-exposure to As and PSNPs exhibited conspicuous renal structural damage and pathological changes, accompanied by renal tissue fibrosis (increased protein expression of Collagen I and α-SMA and deposition of collagen fibers), whereas alone exposure to As or PSNPs does not exhibit nephrotoxicity. Subsequently, our results further showed that combined action of As and PSNPs induced mitochondrial oxidative damage and impaired mitochondrial dynamic balance. Furthermore, co-treatment with As and PSNPs activated NCOA4-mediated ferritinophagy and ferroptosis in mice kidney and TCMK-1 cells, which was confirmed by the changes in the expression of ferritinophagy and ferroptosis related indicators (NCOA4, LC3, ATG5, ATG7, FTH1, FTL, GPX4, SLC7A11, FSP1, ACSL4 and PTGS2). Meaningfully, pretreatment with the mtROS-targeted scavenger Mito-TEMPO significantly attenuated As and PSNPs co-exposure induced mitochondrial damage, ferritinophagy and ferroptosis. In conclusion, these findings demonstrated that mtROS-dependent ferritinophagy and ferroptosis are important factors in As and PSNPs co-exposure induced kidney injury and fibrosis. This study provides a new insight into the study of combined toxicity of nanoplastics and heavy metal pollutants.

Isorhamnetin ameliorates cisplatin-induced acute kidney injury in mice by activating SLPI-mediated anti-inflammatory effect in macrophage

Objective Isorhamnetin (IH) has been reported to have significant anti-inflammatory effects in various diseases, but its role and mechanism in AKI remain unclear. This study aimed to explore the potential role and mechanism of isorhamnetin in inhibiting macrophage related inflammation and improving AKI injury. Methods We established an AKI mouse model by intraperitoneal injection of cisplatin in vivo, and constructed an inflammatory cell model by stimulating RAW264.7 cells with LPS. Creatinine and urea nitrogen were measured to evaluate the changes of renal function in AKI mice. The changes of renal pathological structure were observed by H&E staining. The inflammatory factor-related proteins and RNA expression levels were detected by Western blot and real time PCR. Results Isorhamnetin protected the kidney from cisplatin induced AKI and significantly inhibited the mRNA and protein levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) both in AKI kidney and LPS-stimulated RAW264.7 cells. Interestingly, the data also demonstrated that isorhamnetin significantly upregulated the expression of secretory leukocyte peptidase inhibitor (SLPI), an anti-inflammatory factor, in AKI kidney and LPS-stimulated macrophages, as well as inhibited the M1 macrophage and activated M2 macrophage in vitro. Blocking of SLPI by siRNA activated Mincle-associated inflammatory signaling in macrophages, and the inhibitory effect of isorhamnetin on inflammation was significantly attenuated. Conclusion Isorhamnetin inhibits macrophage inflammation and protects kidney in AKI may be related to downregulating Mincle/Syk/NF-κB-maintained macrophage phenotype by activating SLPI.

Maresin-1 Attenuates Sepsis-Associated Acute Kidney Injury via Suppressing Inflammation, Endoplasmic Reticulum Stress and Pyroptosis by Activating the AMPK/SIRT3 Pathway.

Sepsis-associated acute kidney injury (SA-AKI) is a common complication in patients with sepsis, triggering high morbidity and mortality. Maresin-1 (MaR1) is a pro-resolution lipid mediator that promotes the resolution of acute inflammation and protects organs from inflammation. In this study, we established an SA-AKI model using cecal ligation and puncture (CLP) and investigated the effect and mechanism of MaR1. The blood and kidneys were harvested 24 hours after surgery. The blood biochemical/routine indicators, renal function, SA-AKI-related pathophysiological processes, and AMPK/SIRT3 signaling in septic mice were observed by histological staining, immunohistochemical staining, Western blot, qPCR, ELISA and TUNEL Assay. MaR1 treatment alleviated kidney injury in septic mice, reflected in improved pathological changes in renal structure and renal function. MaR1 treatment decreased the levels of serum creatinine (sCr) and blood urea nitrogen (BUN) and the expressions of KIM-1, NGAL and TIMP-2, which were related to kidney injury, while inhibited the expressions of inflammatory factors TNF-α, IL-1β and IL-6. The expression of endoplasmic reticulum stress-related indicators p-PERK/PERK, GRP78, p-EIF2α/EIF2α, ATF4, CHOP, and pyroptosis-related indicators Caspase-1, NLRP3, GSDMD, IL-18, and IL-1β also decreased after MaR1 treatment. The mechanism may be related to the activation of the AMPK/SIRT3 signaling pathway, and an AMPK inhibitor (compound C) partially reverses MaR1's protective effects in septic mice. Taken together, these findings suggest that MaR1 may partially ameliorate SA-AKI by activating the AMPK/SIRT3 signaling pathway, providing a potential new perspective for research on SA-AKI.

Agmatine ameliorates diabetes type 2-induced nephropathy in rats

Objective: To assess the nephroprotective potential of agmatine in a rat model of streptozotocin-induced diabetic nephropathy. Methods: A single dose of streptozotocin (40 mg/kg) coupled with a fructose diet induced diabetes in Wistar rats. Agmatine (40 and 80 mg/kg) was administered to rats for 12 weeks. The body weight and fasting blood glucose were measured weekly. Insulin level, urine output, total protein, albumin, blood urea nitrogen, creatinine, and cystatin-C were also determined at the end of the experiment. Furthermore, superoxide dismutase, glutathione, interleukin-1β, interleukin-6, and tumor necrosis factor-alpha were evaluated in kidney tissue. Histopathological study was also performed using hematoxylin and eosin staining. Results: Agmatine at both doses significantly increased final body weight, and lowered fasting blood glucose, urine output, insulin, total protein, albumin, blood urea nitrogen, creatinine, and cystatin-C levels compared with the diabetic group (P < 0.05). Inflammatory markers and antioxidant effect were significantly improved in agmatine-treated rats. Moreover, the histopathological changes in renal structure were ameliorated by agmatine treatment. Conclusions: Agmatine alleviates diabetic nephropathy by improving renal functions and reducing inflammation and oxidative stress. The molecular mechanisms of its nephroprotective actions need to be investigated in future study.

SeMet alleviates AFB1-induced oxidative stress and apoptosis in rabbit kidney by regulating Nrf2//Keap1/NQO1 and PI3K/AKT signaling pathways

The purpose of this study was to explore the protective effect of SeMet on renal injury induced by AFB1 in rabbits and its molecular mechanism. Forty rabbits of 35 days old were randomly divided into control group, AFB1 group (0.3 mg AFB1/kg b.w), 0.2 mg/kg Se + AFB1 group (0.3 mg AFB1/kg b.w + 0.2 mg SeMet/kg feed) and 0.4 mg/kg Se + AFB1 group (0.3 mg AFB1/kg b.w + 0.4 mg SeMet/kg feed). The SeMet treatment group was fed different doses of SeMet diets every day for 21 days. On the 17–21 day, the AFB1 treatment group, the 0.2 mg/kg Se + AFB1 group and the 0.4 mg/kg Se + AFB1 group were administered 0.3 mg AFB1 /kg b.w by gavage (dissolved in 0.5 ml olive oil) respectively. The results showed that AFB1 poisoning resulted in the changes of renal structure, the increase of renal coefficient and serum biochemical indexes, the ascent of ROS and MDA levels, the descent of antioxidant enzyme activity, and the significant down-regulation of Nrf2, HO-1 and NQO1. Besides, AFB1 poisoning increased the number of renal apoptotic cells, rised the levels of PTEN, Bax, Caspase-3 and Caspase-9, and decreased the levels of PI3K, AKT, p-AKT and Bcl-2. In summary, SeMet was added to alleviate the oxidative stress injury and apoptosis of kidney induced by AFB1, and the effect of 0.2 mg/kg Se + AFB1 is better than 0.4 mg/kg Se + AFB1.

Pathomechanisms of Diabetic Kidney Disease

The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. Within each pathway, several mediators contribute to the development of renal structural and functional changes. Some of these mediators, such as inflammatory cytokines, reactive oxygen species, and transforming growth factor β are shared among the different pathways, leading to significant overlap and interaction between them. While current treatment options for DKD have shown advancement over previous strategies, their effectiveness remains somewhat constrained as patients still experience residual risk of disease progression. Therefore, a comprehensive grasp of the molecular mechanisms underlying the onset and progression of DKD is imperative for the continued creation of novel and groundbreaking therapies for this condition. In this review, we discuss the current achievements in fundamental research, with a particular emphasis on individual factors and recent developments in DKD treatment.

The Effect of sub-chronic Linuron Exposure on Thyroid, Liver, and Kidney Function in Male Wistar Rats.

Herbicides are routinely used to control noxious plants. Most of these chemicals may cause toxicity and endocrine disruption in humans and wildlife. This study aimed to evaluate the influence of linuron on thyroid hormone levels and some hepatic and renal parameters and organ (thyroid, liver and kidney) structures to assume their toxicity toward experimental animals and to evaluate the endocrine disrupting capacity of this chemical. Two groups (8 rats each) were used for an in vivo study. The lot I served as control. Lot II was exposed to 40mg/200mg/day pesticide for 50 days. Changes in hepatic and renal parameters and histological structure were investigated in different treated groups. Data from this study showed that linuron altered thyroid function as evidenced by abnormal TSH, T4, and T3 levels. Furthermore, exposure to linuron induces a significant decrease in body weight and a significant increase in aspartate aminotransferase, alanine transaminase, total bilirubin, uric acid, creatinine, glutathione, and malondialdehyde. Previous data were confirmed through the histopathological examination of different organs. The most used phenylurea herbicide, linuron, disrupted thyroid function at a 40mg/200mg/day dose and produced oxidative stress in the liver and kidney in male Wistar rats. The data of this study warrant further investigation.

Association of metabolic syndrome and chronic kidney disease.

The prevalence of kidney disease is increasing rapidly worldwide, reflecting rising rates of obesity, diabetes, and associated metabolic syndrome (MetS). Chronic kidney disease and related comorbidities such as obesity, diabetes, and hypertension place a significant financial burden on healthcare systems. Despite the widespread use of RAAS inhibitors, intensive blood pressure and glycemic control, and newer therapeutic options consisting of sodium/glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, a significant risk of progression to end-stage renal disease remains in the high-risk obese and diabetic population. The MetS is a cluster of cardiovascular risk factors that adversely affect the development and progression of chronic kidney failure. According to the criteria of the World Health Organization, it is defined by visceral adiposity, impaired glucose tolerance or insulin resistance, atherogenic dyslipidemia, raised blood pressure, and microalbuminuria with a albumin-to-creatinine ratio ≥30 mg/g. At molecular level MetS is marked by a proinflammatory state and increased oxidative stress leading to various pathophysiological changes causing endothelial dysfunction and a hypercoagulable state. Because the kidney is a highly vascularized organ, it is especially susceptible for those microvascular changes. Therefore, the MetS and its individual components are associated with the premature development, acceleration, and progression of chronic kidney disease. Therefore, it is becoming increasingly important to elucidate the underlying mechanisms of MetS-associated chronic kidney disease in order to develop new strategies for preventing and slowing the progression of renal disease. In this review, we will elucidate (i) the renal structural, hemodynamic, and metabolic changes that occur in obesity and obesity-related kidney injury; (ii) the clinicopathological characteristics of obesity-related kidney injury, primarily focusing on obesity-associated glomerulopathy; (iii) the potential additional factors or predisposing factors that may turn patients more susceptible to renal structural or functional compensatory failure and subsequent injury.

The protective effect and molecular mechanism of glycyrrhizic acid glycosides against Tripterygium glycosides induced nephrotoxicity based on the RhoA/ROCK1 signalling pathway

Ethnopharmacological relevanceTripterygium glycosides (TG), which are extracted from the traditional Chinese medicine, Tripterygium wilfordii Hook F. (TwHF), has promising applications in the treatment of renal diseases; however, since its active components exerts bidirectional kidney toxicity, its clinical application is severely restricted. Aim of the study:Recent investigations have demonstrated definite toxicity-reducing effects from glycyrrhizic acid glycosides (GA) when combined with TG; however, the mechanism remains unclear. To our knowledge, this is the first study to investigate the specific molecular mechanism by which GA alleviates TG-induced renal toxicity from the perspective of tight junctions. Materials and methodsDynamic analyses, which investigated the changes in kidney toxicity biomarkers for different combinations and concentrations of TG and GA, were conducted for three weeks on SD rats and renal tissue structural changes were examined after three weeks of administration. Additionally, the transcription and translation levels of the relevant tight junctions and RhoA/ROCK1/MLC signalling proteins were analysed in HK-2 cells. ResultsOur study showed that TG can cause transient tubulotoxicity at certain doses, and that the combined application of GA and TG can repair tight junction structures by regulating the key factors in the RhoA/ROCK1/MLC signalling pathway, thus reducing TG-induced nephrotoxicity. ConclusionsOverall, this study provides a new strategy to reduce TG-induced toxicity by protecting renal tight junctions.

Clinical phenotype characteristics and genetic analysis in children with nephronophthisis and related syndromes caused by different gene mutations

To improve the understanding of the clinical phenotypes and genetic characteristics of nephronophthisis (NPHP) and related syndromes in children. A retrospective analysis was performed on the medical data of eight children with NPHP and related syndromes who were diagnosed and treated in the Department of Pediatrics of the Second Hospital of Hebei Medical University, from January 2018 to November 2022. The clinical characteristics and genetic testing results were analyzed. Among these eight children, there were five boys and three girls, with an age of onset ranging from 15 months to 12 years. All 8 children exhibited different degrees of renal function abnormalities when they attended the hospital. Among the eight children, two had the initial symptom of delayed development, two had the initial symptom of anemia, and two were found to have abnormal renal function during physical examination. The extrarenal manifestations included cardiovascular abnormalities in two children, skeletal dysplasia in two children, liver dysfunction in one child, retinitis pigmentosa in one child, and visceral translocation in one child. All eight children had renal structural changes on ultrasound, and four children had mild to moderate proteinuria based on routine urine test. Of all eight children, five had NPHP1 gene mutations and one each had a gene mutation in the NPHP3, IFT140, and TTC21B genes, and four new mutation sites were discovered. Children with NPHP and related syndromes often have the initial symptom of delayed development or anemia, and some children also have extrarenal manifestations. NPHP and related syndromes should be considered for children with unexplained renal dysfunction, and high-throughput sequencing may help to make a confirmed diagnosis.

Mitochondrial homeostasis: a potential target for delaying renal aging.

Mitochondria, which are the energy factories of the cell, participate in many life activities, and the kidney is a high metabolic organ that contains abundant mitochondria. Renal aging is a degenerative process associated with the accumulation of harmful processes. Increasing attention has been given to the role of abnormal mitochondrial homeostasis in renal aging. However, the role of mitochondrial homeostasis in renal aging has not been reviewed in detail. Here, we summarize the current biochemical markers associated with aging and review the changes in renal structure and function during aging. Moreover, we also review in detail the role of mitochondrial homeostasis abnormalities, including mitochondrial function, mitophagy and mitochondria-mediated oxidative stress and inflammation, in renal aging. Finally, we describe some of the current antiaging compounds that target mitochondria and note that maintaining mitochondrial homeostasis is a potential strategy against renal aging.

Diabetic kidney disease: Risk factors, challenges and opportunities in the era of precision medicine

DKD is now recognized as the primary cause of chronic and end-stage-renal disease worldwide. The disease is characterized by changes in renal function and structure, followed by a gradual decline in kidney function, leading to ESRD. Risk factors for DKD include age, sex, race/ethnicity, family history of hyperglycemia and AKI. Recent studies have shown that certain medication classes, such as SGLT-2 inhibitors, can protect the kidneys independent of diabetes control. However, there are still gaps in our understanding of DKD, and its diagnosis is subjective due to the lack of a noninvasive biomarker. This makes it challenging to design clinical trials to identify effective treatments for the disease. Our review article aims to provide information on basic mechanisms of DKD, various treatment strategies and challenges by using personalized approaches to diagnosis and prevention.

Protective Effect of Klotho on Acute Kidney Injury Caused by Contrast Agents

Contrast-induced nephropathy (CIN) is currently the third leading cause of iatrogenic renal failure. This research mainly explores the protective effect of Klotho on CIN. Klotho (10 ng/g) was administered after the establishment of a CIN mouse model, and the changes of tissue structure and renal function were observed, and the Wnt/β-catenin pathway and senescence-related factors were detected. Compared with the control group, the brush border of renal tubular epithelial cells disappeared, cytoplasmic vacuole-like changes, renal tubular dilatation, and renal function were significantly reduced in the model group. Klotho treatment can effectively alleviate changes in renal tubular epithelial structure and function. Compared with the model group, Klotho treatment can obviously inhibit the expression of P27 and P53, and promote the expression of Sirt1 and Bmi-1, and Klotho can regulate the Wnt/β-catenin pathway. Exogenous Klotho can slow down nephrocyte senescence by regulating the Wnt/β-catenin pathway, thereby protecting kidney.

Inhibition of ACSF2 protects against renal ischemia/reperfusion injury via mediating mitophagy in proximal tubular cells.

Acute kidney injury (AKI) is a prevalent clinical condition caused by sepsis and ischemia reperfusion (IR) injury. The principal driver of IR-induced AKI involves renal tubular structural changes triggered by the impairment of function in renal tubular cells. The target gene, Acyl-CoA Synthetase Family Member 2 (ACSF2), was retrieved from the GEO database based on high specific expression in renal tubular cells and location in mitochondria. Here, we substantiate that ACSF2 is specifically localized in the mitochondria of the renal tubular epithelium. Functionally silencing ACSF2 in HK2 cells enhanced hypoxia-reoxygenation (HR)-induced mitophagy, restored mitochondrial function and decreased the production of mitochondrial superoxide. Our study demonstrated that these effects were reversed by silencing Bcl-2 19-kDa interacting protein 3 (BNIP3), a receptor regulating mitophagy. In vivo, ACSF2 knockdown significantly enhanced IR-induced mitophagy and improved renal function in mice with IR injury. Conversely, BNIP3 knockdown inhibited mitophagy and exacerbated renal damage in ACSF2-knockdown mice with IR injury. In conclusion, our study demonstrated that inhibition of ACSF2 enhances mitophagy, restoring mitochondrial function and protects against IR-induced AKI, providing a new target and potential strategy for therapy.

3D autofluorescence imaging of hydronephrosis and renal anatomical structure using cryo-micro-optical sectioning tomography.

Rationale: Mesoscopic visualization of the main anatomical structures of the whole kidney in vivo plays an important role in the pathological diagnosis and exploration of the etiology of hydronephrosis. However, traditional imaging methods cannot achieve whole-kidney imaging with micron resolution under conditions representing in vivo perfusion. Methods: We used in vivo cryofixation (IVCF) to fix acute obstructive hydronephrosis (unilateral ureteral obstruction, UUO), chronic spontaneous hydronephrosis (db/db mice), and their control mouse kidneys for cryo-micro-optical sectioning tomography (cryo-MOST) autofluorescence imaging. We quantitatively assessed the kidney-wide pathological changes in the main anatomical structures, including hydronephrosis, renal subregions, arteries, veins, glomeruli, renal tubules, and peritubular functional capillaries. Results: By comparison with microcomputed tomography imaging, we confirmed that IVCF can maintain the status of the kidney in vivo. Cryo-MOST autofluorescence imaging can display the main renal anatomical structures with a cellular resolution without contrast agents. The hydronephrosis volume reached 26.11 ± 6.00 mm3 and 13.01 ± 3.74 mm3 in 3 days after UUO and in 15-week-old db/db mouse kidneys, respectively. The volume of the cortex and inner stripe of the outer medulla (ISOM) increased while that of the inner medulla (IM) decreased in UUO mouse kidneys. Db/db mice also showed an increase in the volume of the cortex and ISOM volume but no atrophy in the IM. The diameter of the proximal convoluted tubule and proximal straight tubule increased in both UUO and db/db mouse kidneys, indicating that proximal tubules were damaged. However, some renal tubules showed abnormal central bulge highlighting in the UUO mice, but the morphology of renal tubules was normal in the db/db mice, suggesting differences in the pathology and severity of hydronephrosis between the two models. UUO mouse kidneys also showed vascular damage, including segmental artery and vein atrophy and arcuate vein dilation, and the density of peritubular functional capillaries in the cortex and IM was reduced by 37.2% and 49.5%, respectively, suggesting renal hypoxia. In contrast, db/db mouse kidneys showed a normal vascular morphology and peritubular functional capillary density. Finally, we found that the db/db mice displayed vesicoureteral reflux and bladder overactivity, which may be the cause of hydronephrosis formation. Conclusions: We observed and compared main renal structural changes in hydronephrosis under conditions representing in vivo perfusion in UUO, db/db, and control mice through cryo-MOST autofluorescence imaging. The results indicate that cryo-MOST with IVCF can serve as a simple and powerful tool to quantitatively evaluate the in vivo pathological changes in three dimensions, especially the distribution of body fluids in the whole kidney. This method is potentially applicable to the three-dimensional visualization of other tissues, organs, and even the whole body, which may provide new insights into pathological changes in diseases.

Calcitriol Reduces the Inflammation, Endothelial Damage and Oxidative Stress in AKI Caused by Cisplatin.

Cisplatin treatment is one of the most commonly used treatments for patients with cancer. However, thirty percent of patients treated with cisplatin develop acute kidney injury (AKI). Several studies have demonstrated the effect of bioactive vitamin D or calcitriol on the inflammatory process and endothelial injury, essential events that contribute to changes in renal function and structure caused by cisplatin (CP). This study explored the effects of calcitriol administration on proximal tubular injury, oxidative stress, inflammation and vascular injury observed in CP-induced AKI. Male Wistar Hannover rats were pretreated with calcitriol (6 ng/day) or vehicle (0.9% NaCl). The treatment started two weeks before i.p. administration of CP or saline and was maintained for another five days after the injections. On the fifth day after the injections, urine, plasma and renal tissue samples were collected to evaluate renal function and structure. The animals of the CP group had increased plasma levels of creatinine and of fractional sodium excretion and decreased glomerular filtration rates. These changes were associated with intense tubular injury, endothelial damage, reductions in antioxidant enzymes and an inflammatory process observed in the renal outer medulla of the animals from this group. These changes were attenuated by treatment with calcitriol, which reduced the inflammation and increased the expression of vascular regeneration markers and antioxidant enzymes.