Exploiting the neonatal crystallizable fragment receptor to treat kidney disease.

The neonatal Fc receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been utilized in many disease treatments including a new class of agents that were developed to inhibit FcRn for treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to utilize FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefit, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss what renal diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases.

miR-4645-3p attenuates podocyte injury and mitochondrial dysfunction in diabetic kidney disease by targeting Cdk5.

Podocyte injury plays a critical role in the progression of diabetic kidney disease (DKD), but the underlying cellular and molecular mechanisms remain poorly understanding. MicroRNAs (miRNAs) can disrupt gene expression by inducing translation inhibition and mRNA degradation, and recent evidence has shown that miRNAs may play a key role in many kidney diseases. In this study, we identified miR-4645-3p by global transcriptome expression profiling as one of the major downregulated miRNAs in high glucose-cultured podocytes. Moreover, whether DKD patients or STZ-induced diabetic mice, expression of miR-4645-3p was also significantly decreased in kidney. In the podocytes cultured by normal glucose, inhibition of miR-4645-3p expression promoted mitochondrial damage and podocyte apoptosis. In the podocytes cultured by high glucose (30 mM glucose), overexpression of miR-4645-3p significantly attenuated mitochondrial dysfunction and podocyte apoptosis induced by high glucose. Furthermore, we found that miR-4645-3p exerted protective roles by targeting Cdk5 inhibition. In vitro, miR-4645-3p obviously antagonized podocyte injury by inhibiting overexpression of Cdk5. In vivo of diabetic mice, podocyte injury, proteinuria, and impaired renal function were all effectively ameliorated by treatment with exogenous miR-4645-3p. Collectively, these findings demonstrate that miR-4645-3p can attenuate podocyte injury and mitochondrial dysfunction in DKD by targeting Cdk5. Sustaining the expression of miR-4645-3p in podocytes may be a novel strategy to treat DKD.

The role of long non-coding RNAs in the development of diabetic kidney disease and the involved clinical application.

Diabetic kidney disease (DKD), one of the common microvascular complications of diabetes, is increasing in prevalence worldwide and can lead to End-stage renal disease. However, there are still gaps in our understanding of the pathophysiology of DKD, and both current clinical diagnostic methods and treatment strategies have drawbacks. According to recent research, long non-coding RNAs (lncRNAs) are intimately linked to the developmental process of DKD and could be viable targets for clinical diagnostic decisions and therapeutic interventions. Here, we review recent insights gained into lncRNAs in pathological changes of DKD such as mesangial expansion, podocyte injury, renal tubular injury, and interstitial fibrosis. We also discuss the clinical applications of DKD-associated lncRNAs as diagnostic biomarkers and therapeutic targets, as well as their limitations and challenges, to provide new methods for the prevention, diagnosis, and treatment of DKD.

Podocyte-Specific Deletion of MCP-1 Fails to Protect against Angiotensin II- or Adriamycin-Induced Glomerular Disease.

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.

Boerhavia diffusa attenuates podocyte injury in rats with adenine induced chronic kidney disease by enhancing nephrin expression.

Nephrin is a transmembrane protein that maintains the slit diaphragm of renal podocyte. In chronic kidney disease (CKD), podocyte effacement causes damage to glomerular basement membrane barrier leading to proteinuria. Boerhavia diffusa, (BD), an Ayurveda herb, is used in treatment of various diseases particularly in relation to the urinary system. This study attempts to evaluate the effect of ethanolic extract of BD on the expression of nephrin in adenine induced CKD rats. CKD was induced in Wistar albino rats using adenine (600/mg/kg, orally for 10 days). CKD rats were treated with BD (400/mg/kg) and pirfenidone (500/mg/kg) orally for 14 days. The kidneys were harvested from euthanized animals and processed for histopathology, electron microscopy and immunohistochemistry, gene and protein expression of nephrin. Diseased rats treated with BD and pirfenidone showed reduction in the thickening of renal basement membranes and reduced haziness in brush border of PCT and glomeruli. Nephrin gene and protein expressions were higher in BD and pirfenidone treated group when compared to the disease control group. The structural and functional damage brought on by adenine-induced nephrotoxicity was countered by protective action of BD by up regulating the expression of nephrin. Therefore, BD can be utilized as a nutraceutical for the prevention and treatment of CKD.

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.

[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.

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.

Genetic or pharmacologic blockade of mPGES-2 attenuates renal lipotoxicity and diabetic kidney disease by targeting Rev-Erbα/FABP5 signaling.

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and no specific drugs are clinically available. We have previously demonstrated that inhibiting microsomal prostaglandin E synthase-2 (mPGES-2) alleviated type 2 diabetes by enhancing ß cell function and promoting insulin production. However, the involvement of mPGES-2 in DKD remains unclear. Here, we aimed to analyze the association of enhanced mPGES-2 expression with impaired metabolic homeostasis of renal lipids and subsequent renal damage. Notably, global knockout or pharmacological blockage of mPGES-2 attenuated diabetic podocyte injury and tubulointerstitial fibrosis, thereby ameliorating lipid accumulation and lipotoxicity. These findings were further confirmed in podocyte- or tubule-specific mPGES-2-deficient mice. Mechanistically, mPGES-2 and Rev-Erbα competed for heme binding to regulate fatty acid binding protein 5 expression and lipid metabolism in the diabetic kidney. Our findings suggest a potential strategy for treating DKD via mPGES-2 inhibition.

Development and Characterization of a Novel FVB-PrkdcR2140C Mouse Model for Adriamycin-Induced Nephropathy.

The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the PrkdcR2140C polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of ADR nephropathy in the FVB/N strain has yet to be conducted. Our research aimed to create a novel mouse model, the FVB-PrkdcR2140C, by introducing PrkdcR2140C into the FVB/NJcl (FVB) strain. Our study showed that FVB-PrkdcR2140C mice developed severe renal damage when exposed to ADR, as evidenced by significant albuminuria and tubular injury, exceeding the levels observed in C57BL/6J (B6)-PrkdcR2140C. This indicates that the FVB/N genetic background, in combination with the R2140C mutation, strongly predisposes mice to ADR nephropathy, highlighting the influence of genetic background on disease susceptibility. Using RNA sequencing and subsequent analysis, we identified several genes whose expression is altered in response to ADR nephropathy. In particular, Mmp7, Mmp10, and Mmp12 were highlighted for their differential expression between strains and their potential role in influencing the severity of kidney damage. Further genetic analysis should lead to identifying ADR nephropathy modifier gene(s), aiding in early diagnosis and providing novel approaches to kidney disease treatment and prevention.

Zinc oxide nanoparticles prevent the onset of diabetic nephropathy by inhibiting multiple pathways associated with oxidative stress.

BACKGROUND: Zinc deficiency is strongly correlated with prolonged diabetes mellitus and diabetic nephropathy (DN). Previously, glucose-lowering, insulinomimetic, and ß-cell proliferative activities of zinc oxide nanoparticles (ZON) have been reported. Considering these pleiotropic effects, we hypothesized that ZON modulates multiple cellular pathways associated with necroptosis, inflammation, and renal fibrosis, which are involved in progressive loss of renal function. AIM: This study evaluated the effect of ZON on renal function, leading to the alleviation of DN in streptozotocin (STZ)-induced type 1 diabetic Wistar rats and proposed a probable mechanism for its activity. METHODS: Wistar rats (n = 6/group) were used as healthy controls, diabetic controls, diabetic rats treated with ZON (1, 3, and 10 mg/kg), and insulin controls. Urine and serum biochemical parameters, glomerular filtration rate (GFR), and renal histology were also evaluated. Cultured E11 podocytes were evaluated in vitro for markers of oxidative stress, proteins associated with the loss of renal function, and genes associated with renal damage. KEY FINDINGS: STZ-treated rats receiving oral doses of ZON showed enhanced renal function, with no histological alterations in the kidney tissue. ZON inhibited the TGF-ß/Samd3 pathway in renal fibrosis; blocked Ripk1/Ripk3/Mlkl mediated necroptosis and protected against hyperglycemia-induced pyroptosis. In E11 podocytes, ZON reduced oxidative stress under high glucose conditions and retained podocyte-specific proteins. SIGNIFICANCE: A probable mechanism by which ZON prevents DN has been proposed, suggesting its use as a complementary therapeutic agent for the treatment of diabetic complications. To the best of our knowledge, this is the first study to demonstrate the in vitro effects of ZON in cultured podocytes.

Promoting mitochondrial dynamics by inhibiting the PINK1-PRKN pathway to relieve diabetic nephropathy.

Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function and molecular pathways are highly conserved between mammalian podocytes and Drosophila nephrocytes; therefore, we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes from flies on a high-sucrose diet showed a significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocyte filtration structure, known as the slit diaphragm, was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunctional mitochondria. Regulating mitochondrial dynamics by either genetic modification of the Pink1-Park (mammalian PINK1-PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1-Park-mediated mitophagy and associated control of mitochondrial dynamics in diabetic nephropathy, and demonstrate that targeting this pathway might provide therapeutic benefits for type 2 diabetic nephropathy.

Activation of the IL-6/STAT3 pathway contributes to the pathogenesis of membranous nephropathy and is a target for Mahuang Fuzi and Shenzhuo Decoction (MFSD) to repair podocyte damage.

BACKGROUND: Primary membranous nephropathy (PMN) is an autoimmune glomerular disease. IL-6 is a potential therapeutic target for PMN. Previous clinical studies have demonstrated the effectiveness of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in treating membranous nephropathy. However, the mechanism of action of MFSD remains unclear. METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed. RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect. CONCLUSION: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.

C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis.

Podocytes are essential to maintaining the integrity of the glomerular filtration barrier, but they are frequently affected in lupus nephritis (LN). Here, we show that the significant upregulation of Drp1S616 phosphorylation in podocytes promotes mitochondrial fission, leading to mitochondrial dysfunction and podocyte injury in LN. Inhibition or knockdown of Drp1 promotes mitochondrial fusion and protects podocytes from injury induced by LN serum. In vivo, pharmacological inhibition of Drp1 reduces the phosphorylation of Drp1S616 in podocytes in lupus-prone mice. Podocyte injury is reversed when Drp1 is inhibited, resulting in the alleviation of proteinuria. Mechanistically, complement component C5a (C5a) upregulates the phosphorylation of Drp1S616 and promotes mitochondrial fission in podocytes. Moreover, the expression of C5a receptor 1 (C5aR1) is notably upregulated in podocytes in LN. C5a-C5aR1 axis-controlled phosphorylation of Drp1S616 and mitochondrial fission are substantially suppressed when C5aR1 is knocked down by siRNA. Moreover, lupus-prone mice treated with C5aR inhibitor show reduced phosphorylation of Drp1S616 in podocytes, resulting in significantly less podocyte damage. Together, this study uncovers a novel mechanism by which the C5a-C5aR1 axis promotes podocyte injury by enhancing Drp1-mediated mitochondrial fission, which could have significant implications for the treatment of LN.

Analysis of glomerular deposition of IgM and C3 in patients with podocytopathies.

Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are the main causes of nephrotic syndrome in the world. The complement system appears to play an important role in the pathogenesis of these diseases. To evaluate the deposition of immunoglobulins and particles of the complement system in renal biopsies of patients with FSGS and MCD and relate to laboratory data, we selected 59 renal biopsies from patients with podocytopathies, 31 from patients with FSGS and 28 with MCD. Epidemiological, clinical, laboratory information and the prognosis of these patients were evaluated. Analysis of the deposition of IgM, IgG, C3, C1q and C4d in renal biopsies was performed. We related IgM and C3 deposition with laboratory parameters. Statistical analysis was performed using GraphPad Prism version 7.0. Glomerular deposition of IgM was significantly higher in the FSGS group, as was codeposition of IgM and C3. The clinical course of patients and laboratory data were also worse in cases of FSGS, with a higher percentage progressing to chronic kidney disease and death. Patients with C3 deposition had significantly higher mean serum creatinine and significantly lower eGFR, regardless of disease. Patients with FSGS had more IgM and C3 deposition in renal biopsies, worse laboratory data and prognosis than patients with MCD. C3 deposition, both in FSGS and MCD, appears to be related to worsening renal function.

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.

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.