[Jianpi Zishen granule inhibits podocyte autophagy in systemic lupus erythematosus: a network pharmacology and clinical study].

OBJECTIVE: To explore the therapeutic mechanism of Jianpi Zishen (JPZS) granules for systemic lupus erythematosus(SLE) in light of podocyte autophagy regulation. METHODS: TCMSP, GeneCards, OMIM, and TTD databases were used to obtain the targets of JPZS granules, SLE, and podocyte autophagy. The protein-protein interaction network was constructed using Cytoscape, and the key active ingredients and targets were screened for molecular docking. In the clinical study, 46 patients with SLE were randomized into two groups to receive baseline treatment with prednisone acetate and mycophenolate mofetil (control group) and additional treatment with JPZS granules (observation group) for 12 weeks, with 10 healthy volunteers as the healthy control group. Urinary levels of nephrin and synaptopodin of the patients were detected with ELISA. Western blotting was performed to determine peripheral blood levels of p-JAK1/JAK1, p-STAT1/STAT1, LC3II/LC3I, and p62 proteins of the participants. RESULTS: Four key active ingredients and 5 core target genes (STAT1, PIK3CG, MAPK1, PRKCA, and CJA1) were obtained, and enrichment analysis identified the potentially involved signaling pathways including AGE-RAGE, JAK/STAT, EGFR, and PI3K/Akt. Molecular docking analysis showed that STAT1 was the most promising target protein with the highest binding activity, suggesting its role as an important mediator for signal transduction after JPZS granule treatment. In the 43 SLE patients available for analysis, treatment with JPZS granule significantly reduced serum levels of p-JAK1/JAK1, p-STAT1/STAT1, and LC3II/LC3I (P < 0.05 or 0.01), increased the protein level of P62 (P < 0.05), and reduced urinary levels of nephrin and synaptopodin (P < 0.05). CONCLUSION: The therapeutic effect of JPZS granules on SLE is mediated probably by coordinated actions of quercetin, kaempferol, ß-sitosterol, and isorhamnetin on their target gene STAT1 to inhibit the JAK/STAT pathway, thus suppressing autophagy and alleviating podocyte injuries in SLE.

Zyxin is important for the stability and function of podocytes, especially during mechanical stretch.

Podocyte detachment due to mechanical stress is a common issue in hypertension-induced kidney disease. This study highlights the role of zyxin for podocyte stability and function. We have found that zyxin is significantly up-regulated in podocytes after mechanical stretch and relocalizes from focal adhesions to actin filaments. In zyxin knockout podocytes, we found that the loss of zyxin reduced the expression of vinculin and VASP as well as the expression of matrix proteins, such as fibronectin. This suggests that zyxin is a central player in the translation of mechanical forces in podocytes. In vivo, zyxin is highly up-regulated in patients suffering from diabetic nephropathy and in hypertensive DOCA-salt treated mice. Furthermore, zyxin loss in mice resulted in proteinuria and effacement of podocyte foot processes that was measured by super resolution microscopy. This highlights the essential role of zyxin for podocyte maintenance in vitro and in vivo, especially under mechanical stretch.

GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.

Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome.

Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFß1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.

Comparative analysis of effects of conditioned mediums obtained from 2D or 3D cultured mesenchymal stem cells on kidney functions of diabetic rats: Early intervention could potentiate transdifferentiation of parietal epithelial cell into podocyte precursors.

AIM: The secretome of mesenchymal stem cells (MSCs) could be a potential therapeutic intervention for diabetes and associated complications like nephropathy. This study aims to evaluate the effects of conditioned mediums (CMs) collected from umbilical cord-derived MSCs incubated under 2-dimensional (2D) or 3D culture conditions on kidney functions of rats with type-I diabetes (T1D). MAIN METHODS: Sprague-Dawley rats were treated with 20 mg/kg streptozocin for 5 consecutive days to induce T1D, and 12 doses of CMs were applied intraperitoneally for 4 weeks. The therapeutic effects of CMs were comparatively investigated by biochemical, physical, histopathological, and immunohistochemical analysis. KEY FINDINGS: 3D-CM had significantly higher total protein concentration than the 2D-CM Albumin/creatinine ratios of both treatment groups were significantly improved in comparison to diabetes. Light microscopic evaluations showed that glomerular and cortical tubular damages were significantly ameliorated in only the 3D-CM applied group compared to the diabetes group, which were correlated with transmission electron microscopic observations. The nephrin and synaptopodin expressions increased in both treatment groups compared to diabetes. The WT1, Ki-67, and active caspase-3 expressions in glomeruli and parietal layers of the treatment groups suggest that both types of CMs suppress apoptosis and promote possible parietal epithelial cells' (PECs') transdifferentiation towards podocyte precursor cells by switching on WT1 expression in parietal layer rather than inducing new cell proliferation. SIGNIFICANCE: 3D-CM was found to be more effective in improving kidney functions than 2D-CM by ameliorating glomerular damage through the possible mechanism of transdifferentiation of PECs into podocyte precursors and suppressing glomerular apoptosis.

Dapagliflozin prevents kidney podocytes pyroptosis via miR-155-5p/HO-1/NLRP3 axis modulation.

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1ß in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

LncRNA AA465934 Improves Podocyte Injury by Promoting Tristetraprolin-Mediated HMGB1 DownRegulation in Diabetic Nephropathy.

Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined. Furthermore, AA465934 and autophagy levels, as well as tristetraprolin (TTP) and high mobility group box 1 (HMGB1) expression changes were detected. We also observed podocyte injury and the binding ability of TTP to E3 ligase proviral insertion in murine lymphomas 2 (PIM2), AA465934, or HMGB1. According to the results, AA465934 improved DN progression and podocyte damage in T2DN mice. In addition, AA465934 bound to TTP and inhibited its degradation by blocking TTP-PIM2 binding. Notably, TTP knock-down blocked the ameliorating effects of AA465934 and TTP bound HMGB1 mRNA, reducing its expression. Overexpression of HMGB1 inhibited the ability of AA465934 and TTP to improve podocyte injury. Furthermore, AA465934 bound TTP, inhibiting TTP-PIM2 binding, thereby suppressing TTP degradation, downregulating HMGB1, and reversing autophagy downregulation, ultimately alleviating HG-mediated podocyte injury and DN. Based on these findings, we deduced that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.

Inhibition of RAC attenuates Adriamycin-induced podocyte injury.

Minimal Change Disease (MCD), which is associated with podocyte injury, is the leading cause of nephrotic syndrome in children. A considerable number of patients experience relapses and require prolonged use of prednisone and immunosuppressants. Multi-drug resistance and frequent relapses can lead to disease progression to focal and segmental glomerulosclerosis (FSGS). To identify potential targets for therapy of podocyte injury, we examined microarray data of mRNAs in glomerular samples from both MCD patients and healthy donors, obtained from the GEO database. Differentially expressed genes (DEGs) were used to construct the protein-protein interactions (PPI) network through the application of the search tool for the retrieval of interacting genes (STRING) tool. The most connected genes in the network were ranked using cytoHubba. 16 hub genes were selected and validated by qRT-PCR. RAC2 was identified as a potential therapeutic target for further investigation. By downregulating RAC2, Adriamycin (ADR)-induced human podocytes (HPCs) injury was attenuated. EHT-1864, a small molecule inhibitor that targets the RAC (RAC1, RAC2, RAC3) family, proved to be more effective than RAC2 silencing in reducing HPCs injury. In conclusion, our research suggests that EHT-1864 may be a promising new molecular drug candidate for patients with MCD and FSGS.

Transcriptomic profile of human iPSC-derived podocyte-like cells exposed to a panel of xenobiotics.

Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular barrier causing permanent damage leading to progressive chronic kidney disease. Matured podocytes have little proliferative potential, which makes them critical cells from a health perspective, but also challenging cells to maintain in vitro. Differentiating podocyte-like cells from induced pluripotent stem cells (iPSC) provides a novel and continuous source of cells. Here, we investigated the effect of a 24-h exposure to eight compounds, including the known glomerular toxins doxorubicin and pamidronate, on transcriptomic alterations in iPSC derived podocytes. Doxorubicin (50 nM), pamidronate (50 µM), sodium arsenite (10 µM), and cyclosporine A (15 µM) had a strong impact on the transcriptome, gentamicin (450 µg/ml), lead chloride (15 µM) and valproic acid (500 µM) had a mild impact and busulfan (50 µM) exhibited no impact. Gene alterations and pathways analysis provided mechanistic insight for example, doxorubicin exposure affected the p53 pathway and dedifferentiation, pamidronate activated several pathways including HIF1alpha and sodium arsenite up-regulated oxidative stress and metal responses. The results demonstrate the applicability of iPSC derived podocytes for toxicological and mechanistic investigations.

The role of podocytes in lupus nephritis: Insights and implications.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus, with high mortality rates despite medical advancements. The complexity of its pathogenesis, including the pivotal role of podocytes - kidney-localized cells - remains a challenge, lacking effective treatments and biomarkers. Recent studies highlight the significant contribution of these cells to LN's development, particularly through their immune-related functions and interaction with other kidney cells. This new understanding opens possibilities for targeted therapies aimed at these cellular mechanisms. This review aims to summarize these recent developments, shedding light on the intricate involvement of podocytes in LN and potential avenues for innovative treatments.

IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions.

Genetic variants in the protein-coding regions of APOL1 are associated with an increased risk and progression of chronic kidney disease (CKD) in African Americans. Hypoxia exacerbates CKD progression by stabilizing HIF-1α, which induces APOL1 transcription in kidney podocytes. However, the contribution of additional mediators to regulating APOL1 expression under hypoxia in podocytes is unknown. Here, we report that a transient accumulation of HIF-1α in hypoxia is sufficient to upregulate APOL1 expression in podocytes through a cGAS/STING/IRF3-independent pathway. Notably, IFI16 ablation impedes hypoxia-driven APOL1 expression despite the nuclear accumulation of HIF-1α. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1α. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer/promoter region, showing increased HIF-1α binding to HREs located in the APOL1 gene enhancer. Luciferase reporter assays confirm the role of these HREs in transcriptional activation. Chromatin immunoprecipitation (ChIP)-qPCR assays demonstrate that IFI16 is not recruited to HREs, and IFI16 deletion reduces HIF-1α binding to APOL1 HREs. RT-qPCR analysis indicates that IFI16 selectively affects APOL1 expression, with a negligible impact on other hypoxia-responsive genes in podocytes. These findings highlight the unique contribution of IFI16 to hypoxia-driven APOL1 gene expression and suggest alternative IFI16-dependent mechanisms regulating APOL1 gene expression under hypoxic conditions.

Long noncoding RNA Glis2 regulates podocyte mitochondrial dysfunction and apoptosis in diabetic nephropathy via sponging miR-328-5p.

Podocyte apoptosis exerts a crucial role in the pathogenesis of DN. Recently, long noncoding RNAs (lncRNAs) have been gradually identified to be functional in a variety of different mechanisms associated with podocyte apoptosis. This study aimed to investigate whether lncRNA Glis2 could regulate podocyte apoptosis in DN and uncover the underlying mechanism. The apoptosis rate was detected by flow cytometry. Mitochondrial membrane potential (ΔΨM) was measured using JC-1 staining. Mitochondrial morphology was detected by MitoTracker Deep Red staining. Then, the histopathological and ultrastructure changes of renal tissues in diabetic mice were observed using periodic acid-Schiff (PAS) staining and transmission electron microscopy. We found that lncRNA Glis2 was significantly downregulated in high-glucose cultured podocytes and renal tissues of db/db mice. LncRNA Glis2 overexpression was found to alleviate podocyte mitochondrial dysfunction and apoptosis. The direct interaction between lncRNA Glis2 and miR-328-5p was confirmed by dual luciferase reporter assay. Furthermore, lncRNA Glis2 overexpression alleviated podocyte apoptosis in diabetic mice. Taken together, this study demonstrated that lncRNA Glis2, acting as a competing endogenous RNA (ceRNA) of miRNA-328-5p, regulated Sirt1-mediated mitochondrial dysfunction and podocyte apoptosis in DN.

Podocyte Ercc1 is indispensable for glomerular integrity.

As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44+CD8+ memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs.

Rutaecarpine protects podocytes in diabetic kidney disease by targeting VEGFR2/NLRP3-mediated pyroptosis.

OBJECTIVE: Diabetic kidney disease (DKD) is the most common cause of the end-stage renal disease, which has limited treatment options. Rutaecarpine has anti-inflammatory effects, however, it has not been studied in DKD. Pyroptosis is a newly discovered mode of podocyte death related to inflammation. This study aimed to explore whether Rutaecarpine can ameliorate DKD and to clarify its possible mechanism. METHODS: In this study, we investigated the effects of Rutaecarpine on DKD using diabetic mice model (db/db mice) and high glucose (HG)-stimulated mouse podocyte clone 5 (MPC5) cells. Quantitative reverse transcription polymerase chain reaction and western blot were performed to detect the related gene and protein levels. We applied pharmacological prediction, co-immunoprecipitation assay, cellular thermal shift assay, surface plasmon resonance to find the target and pathway of the substances. Gene knockdown experiments confirmed this view in HG-stimulated MPC5 cells. RESULTS: Rutaecarpine significantly reduced proteinuria, histopathological damage, and pyroptosis of podocytes in a dose-dependent manner in db/db mice. Rutaecarpine also protected high glucose induced MPC5 injury in vitro experiments. Mechanistically, Rutaecarpine can inhibit pyroptosis in HG-stimulated MPC5 by reducing the expression of VEGFR2. VEGFR2 is a target of Rutaecarpine in MPC5 cells and directly binds to the pyroptosis initiation signal, NLRP3. VEGFR2-knockdown disrupted the beneficial effects of Rutaecarpine in HG-stimulated MPC5 cells. CONCLUSION: Rutaecarpine inhibits renal inflammation and pyroptosis through VEGFR2/NLRP3 pathway, thereby alleviating glomerular podocyte injury. These findings highlight the potential of Rutaecarpine as a novel drug for DKD treatment.

Apolipoprotein L1 (APOL1) renal risk variant-mediated podocyte cytotoxicity depends on African haplotype and surface expression.

Homozygous Apolipoprotein L1 (APOL1) variants G1 and G2 cause APOL1-mediated kidney disease, purportedly acting as surface cation channels in podocytes. APOL1-G0 exhibits various single nucleotide polymorphisms, most commonly haplotype E150K, M228I and R255K ("KIK"; the Reference Sequence is "EMR"), whereas variants G1 and G2 are mostly found in a single "African" haplotype background ("EIK"). Several labs reported cytotoxicity with risk variants G1 and G2 in KIK or EIK background haplotypes, but used HEK-293 cells and did not verify equal surface expression. To see if haplotype matters in a more relevant cell type, we induced APOL1-G0, G1 and G2 EIK, KIK and EMR at comparable surface levels in immortalized podocytes. G1 and G2 risk variants (but not G0) caused dose-dependent podocyte death within 48h only in their native African EIK haplotype and correlated with K+ conductance (thallium FLIPR). We ruled out differences in localization and trafficking, except for possibly greater surface clustering of cytotoxic haplotypes. APOL1 surface expression was required, since Brefeldin A rescued cytotoxicity; and cytoplasmic isoforms vB3 and vC were not cytotoxic. Thus, APOL1-EIK risk variants kill podocytes in a dose and haplotype-dependent manner (as in HEK-293 cells), whereas unlike in HEK-293 cells the KIK risk variants did not.

Nephrotic syndrome sera induce different transcriptomes in podocytes based on the steroid response.

As the molecular mechanism of nephrotic syndrome remains largely undiscovered, patients continue to be exposed to the pros and cons of uniform glucocorticoid treatment. We explored whether the exposure of in vitro-cultivated podocytes to sera from children with steroid-sensitive or steroid-resistant nephrotic syndrome induces differences in gene expression profiles, which could help to elucidate the pathogenesis of the steroid response. Human immortalized podocytes were cultivated with patient sera for 3 days. After cell lysis, RNA extraction, 3'-mRNA libraries were prepared and sequenced. There were 34 significantly upregulated and 14 downregulated genes (fold difference <0.5 and >2.0, respectively, and false discovery rate-corrected p < 0.05) and 22 significantly upregulated and 6 downregulated pathways (false discovery rate-corrected p < 0.01) in the steroid-sensitive (n = 9) versus steroid-resistant group (n = 4). The observed pathways included upregulated redox reactions, DNA repair, mitosis, protein translation and downregulated cholesterol biosynthesis. Sera from children with nephrotic syndrome induce disease subtype-specific transcriptome changes in human podocytes in vitro. However, further exploration of a larger cohort is needed to verify whether clinically distinct types of nephrotic syndrome or disease activity may be differentiated by specific transcriptomic profiles and whether this information may help to elucidate the pathogenesis of the steroid response.

PGC1-α in diabetic kidney disease: unraveling renoprotection and molecular mechanisms.

Mitochondrial dysfunction represents a pivotal aspect of the pathogenesis and progression of diabetic kidney disease (DKD). Central to the orchestration of mitochondrial biogenesis is the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α), a master regulator with a profound impact on mitochondrial function. In the context of DKD, PGC1-α exhibits significant downregulation within intrinsic renal cells, precipitating a cascade of deleterious events. This includes a reduction in mitochondrial biogenesis, heightened levels of mitochondrial oxidative stress, perturbed mitochondrial dynamics, and dysregulated mitophagy. Concurrently, structural and functional abnormalities within the mitochondrial network ensue. In stark contrast, the sustained expression of PGC1-α emerges as a beacon of hope in maintaining mitochondrial homeostasis within intrinsic renal cells, ultimately demonstrating an impressive renoprotective potential in animal models afflicted with DKD. This comprehensive review aims to delve into the recent advancements in our understanding of the renoprotective properties wielded by PGC1-α. Specifically, it elucidates the potential molecular mechanisms underlying PGC1-α's protective effects within renal tubular epithelial cells, podocytes, glomerular endothelial cells, and mesangial cells in the context of DKD. By shedding light on these intricate mechanisms, we aspire to provide valuable insights that may pave the way for innovative therapeutic interventions in the management of DKD.

The potential role of differentially expressed tRNA-derived fragments in high glucose-induced podocytes.

The prevalence of diabetic kidney disease (DKD) is increasing annually. Damage to and loss of podocytes occur early in DKD. tRNA-derived fragments (tRFs), originating from tRNA precursors or mature tRNAs, are associated with various illnesses. In this study, tRFs were identified, and their roles in podocyte injury induced by high-glucose (HG) treatment were explored. High-throughput sequencing of podocytes treated with HG was performed to identify differentially expressed tRFs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. The expression levels of nephrin, podocin, and desmin were measured in podocytes after overexpression of tRF-1:24-Glu-CTC-1-M2 (tRF-1:24) and concomitant HG treatment. A total of 647 tRFs were identified, and 89 differentially expressed tRFs (|log2FC| ≥ 0.585; p ≤ .05) were identified in the HG group, of which 53 tRFs were downregulated and 36 tRFs were upregulated. The 10 tRFs with the highest differential expression were detected by real-time quantitative polymerase chain reaction (RT-qPCR), and these results were consistent with the sequencing results. GO analysis revealed that the biological process, cellular component, and molecular function terms in which the tRFs were the most enriched were cellular processes, cellular anatomical entities, and binding. KEGG pathway analysis revealed that tRFs may be involved in signaling pathways related to growth hormones, phospholipase D, the regulation of stem cell pluripotency, and T-/B-cell receptors. Overexpression of tRF-1:24, one of the most differentially expressed tRFs, attenuated podocyte injury induced by HG. Thus, tRFs might be potential biomarkers for podocyte injury in DKD.

Hyperglycemia - A culprit of podocyte pathology in the context of glycogen metabolism.

Prolonged disruption in the balance of glucose can result in metabolic disorders. The kidneys play a significant role in regulating blood glucose levels. However, when exposed to chronic hyperglycemia, the kidneys' ability to handle glucose metabolism may be impaired, leading to an accumulation of glycogen. Earlier studies have shown that there can be a significant increase in glucose storage in the form of glycogen in the kidneys in diabetes. Podocytes play a crucial role in maintaining the integrity of filtration barrier. In diabetes, exposure to elevated glucose levels can lead to significant metabolic and structural changes in podocytes, contributing to kidney damage and the development of diabetic kidney disease. The accumulation of glycogen in podocytes is not a well-established phenomenon. However, a recent study has demonstrated the presence of glycogen granules in podocytes. This review delves into the intricate connections between hyperglycemia and glycogen metabolism within the context of the kidney, with special emphasis on podocytes. The aberrant storage of glycogen has the potential to detrimentally impact podocyte functionality and perturb their structural integrity. This review provides a comprehensive analysis of the alterations in cellular signaling pathways that may potentially lead to glycogen overproduction in podocytes.