Establishment and characterization of a mouse model for studying kidney repair in diabetes.

The prognosis of acute kidney injury (AKI) is markedly worse in patients with diabetes. Diabetes not only exaggerates the severity of AKI but also prevent kidney repair or recovery from AKI. Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Specifically, diabetes increases AKI severity, making it difficult to induce the same level of AKI in diabetic and nondiabetic animals to compare their kidney repair. Here, we have identified a time window of 4 days immediately after the completion of streptozotocin (STZ) treatment in mice when blood glucose has yet to rise. Within this time window, renal ischemia-reperfusion injury (IRI) induced the same level of AKI in STZ-treated mice [127.2 ± 12.82 mg/dL blood urea nitrogen (BUN), 2.275 ± 0.4728 serum creatinine] and vehicle solution-treated mice (128.6 ± 11.83 mg/dL BUN, 2.087 ± 0.4748 mg/dL serum creatinine]. By days 5-6, the post-AKI kidney entered into the phase of kidney repair when diabetic hyperglycemia started in STZ-treated mice, providing the opportunity to study the effect of diabetes on kidney repair without affecting initial AKI. In this model, kidney repair was indeed impaired by diabetes (116.5 ± 8.052 mg/dL BUN and 1.382 ± 0.2732 mg/dL serum creatinine in IR + vehicle group; 136.6 ± 8.740 mg/dL BUN and 1.916 ± 0.3756 mg/dL serum creatinine in IR + STZ group). The impairment was associated with decreased tubular cell proliferation and increased tubular cell senescence, peritubular capillary (PTC) rarefaction, inflammation, and 40.90% more interstitial fibrosis.NEW & NOTEWORTHY Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Here, we report a mouse model to investigate the effect of diabetes on kidney repair without affecting initial injury and found that the repair defect is associated with decreased renal tubular cell proliferation and increased tubular cell senescence, PTC rarefaction, inflammation, and interstitial fibrosis.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

Endoplasmic reticulum stress contributes to cisplatin-induced chronic kidney disease via the PERK-PKCδ pathway.

BACKGROUND: Cisplatin is an effective chemotherapeutic drug, but it may induce both acute and chronic kidney problems. The pathogenesis of chronic kidney disease (CKD) associated with cisplatin chemotherapy remains largely unclear. METHODS: Mice and renal tubular cells were subjected to repeated low-dose cisplatin (RLDC) treatment to induce CKD and related pathological changes. The roles of endoplasmic reticulum (ER) stress, PERK, and protein kinase C-δ (PKCδ) were determined using pharmacological inhibitors and genetic manipulation. RESULTS: ER stress was induced by RLDC in kidney tubular cells in both in vivo and in vitro models. ER stress inhibitors given immediately after RLDC attenuated kidney dysfunction, tubular atrophy, kidney fibrosis, and inflammation in mice. In cultured renal proximal tubular cells, inhibitors of ER stress or its signaling kinase PERK also suppressed RLDC-induced fibrotic changes and the expression of inflammatory cytokines. Interestingly, RLDC-induced PKCδ activation, which was blocked by ER stress or PERK inhibitors, suggesting PKCδ may act downstream of PERK. Indeed, suppression of PKCδ with a kinase-dead PKCδ (PKCδ-KD) or Pkcδ-shRNA attenuated RLDC-induced fibrotic and inflammatory changes. Moreover, the expression of active PKCδ-catalytic fragment (PKCδ-CF) diminished the beneficial effects of PERK inhibitor in RLDC-treated cells. Co-immunoprecipitation assay further suggested PERK binding to PKCδ. CONCLUSION: These results indicate that ER stress contributes to chronic kidney pathologies following cisplatin chemotherapy via the PERK-PKCδ pathway.

Treating crescentic glomerulonephritis by targeting macrophages.

Macrophage accumulation in the kidney is associated with the progression of crescentic glomerulonephritis (GN) and is mostly derived from circulating monocytes. FROUNT, a C-C motif chemokine receptor 2 (CCR2)-interacted protein, which is strongly expressed in monocytes/macrophages, enhances macrophage infiltration through CCR2-mediated chemotaxis. In this issue of the journal, Toda et al. reported that disulfiram, an inhibitor of FROUNT, attenuates GN by inhibition of the FROUNT-CCR2 interaction and macrophage migration and activation, suggesting a potential therapeutic role for crescentic GN.

Gasdermin D is involved in switching from apoptosis to pyroptosis in TLR4-mediated renal tubular epithelial cells injury in diabetic kidney disease.

BACKGROUND: Toll-like receptor 4 (TLR4) mediated pathway plays a pivotal role in promoting tubulointerstitial inflammation and contributes to the progression in type 2 diabetic kidney disease (T2DKD). As the first identified key pyroptosis executor, gasdermin D (GSDMD) is activated by caspases and might be the key protein to switch apoptosis to pyroptosis. It remains unclear that role of TLR4 on canonical pyroptosis pathway, and whether GSDMD is involved in switching from apoptosis to pyroptosis in the TLR4-related tubular injury in T2DKD. METHODS: Immunohistochemistry staining was used to detect the expression of pyroptosis-related proteins in renal tissues of T2DKD patients. T2DKD models was induced in TLR4 knockout (TLR4-/-) mice through a high-fat diet combined with streptozotocin. Pyroptosis (caspase-1, GSDMD, interleukin 18(IL-18), interleukin 1ß(IL-1ß)) and apoptosis levels (caspase-3, Bax and Bcl-2) were detected by Western blot. HK-2 cells were cultured under high-glucose (HG) conditions as an in vitro model and then challenged with a TLR4-specific antagonist (TAK-242). GSDMD small interfering RNA (siRNA) and overexpression plasmid were transfected into HK-2 cells to down- or up-regulate GSDMD. The pyroptosis and apoptosis rates were determined by flow cytometry. RESULTS: The expression levels of caspase-1, GSDMD, IL-18 and IL-1ß were increased in renal biopsy tissues of T2DKD patients and GSDMD expression was positively correlated with tubular injury. Silencing GSDMD attenuated HG-induced IL-18, IL-1ß, FN and α-SMA, and reduced pyroptotic cells rate in HK-2 cells. Up-regulation of GSDMD inhibited HG-induced expression of Bax and cleaved caspase-3 and reduced apoptosis rate. TLR4 knockout alleviated tubular injury and interstitial macrophages infiltration, improved impaired renal dysfunction, and decreased the expressions of active N-terminal of GSDMD(GSDMD-N), cleaved caspase-1(cl-caspase-1) and cleaved caspase-3(cl-caspase-3) in T2DKD mice. TLR4 inhibition reduced HG-induced pyroptosis and apoptosis level in HK-2 cells, while GSDMD up-regulation increased pyroptosis rate and decreased apoptosis rate. CONCLUSIONS: TLR4 could exacerbate tubular injury and fibrosis via GSDMD-mediated canonical pyroptosis pathway in T2DKD. Activation of GSDMD could inhibit apoptosis and activate pyroptosis, which may involve the potential switch mechanism between TLR4-mediated pyroptosis and apoptosis in T2DKD.

Pentosan polysulfate ameliorates fibrosis and inflammation markers in SV40 MES13 cells by suppressing activation of PI3K/AKT pathway via miR-446a-3p.

BACKGROUND: Renal fibrosis is a common outcome of various renal damage, including diabetic nephropathy (DN), the leading cause of end-stage renal disease. Currently, there are no effective therapies for renal fibrosis. The present study aimed to determine whether pentosan polysulphate sodium (PPS), a FDA approved medication for interstitial cystitis, protects diabetic renal fibrosis. METHODS: Cell viability and apoptosis were evaluated in mouse mesangial cells (SV40-MES13) after incubating with the advanced glycation end products (AGEs), which play important roles in the pathogenesis of DN. Western blot and ELISA were performed to determine the expression of transforming growth factor-beta1 (TGF-ß1) and fibronectin (FN), two biomarkers of renal fibrosis, as well as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), two biomarkers of inflammation. The miRNA-mRNA regulatory network involved in the phosphatidylinositol 3-kinase (PI3K)/Ser and Thr Kinase (AKT) signalling was investigated by miRNA deep sequencing and validated by RT-PCR and miRNA transfection. RESULTS: AGEs significantly inhibited cell proliferation and promoted cell apoptosis, which was associated with the overexpression of TGF-ß1, FN, IL-6, and TNFα. PPS almost completely reversed AGEs-induced biomarkers of fibrosis and inflammation, and significantly altered the miRNA expression profile in AGEs-treated cells. Notably, the PI3K/AKT signalling was one of the most significantly enriched pathways targeted by PPS-related differentially expressed miRNAs. PPS significantly up-regulated miR-466a-3p, which was shown to target PIK3CA, and mediated the inhibitory effect of PPS on AGEs-induced activation of PI3K/AKT pathway. CONCLUSIONS: The treatment of PPS protected against AGEs-induced toxicity in SV40 MES13 cells via miR-466a-3p-mediated inhibition of PI3K/AKT pathway.

Disparate roles of retinoid acid signaling molecules in kidney disease.

Retinoid acid (RA) is synthesized mainly in the liver and has multiple functions in development, cell differentiation and proliferation, and regulation of inflammation. RA has been used to treat multiple diseases, such as cancer and skin disorders. The kidney is a major organ for RA metabolism, which is altered in the diseased condition. RA is known to have renal-protective effects in multiple animal models of kidney disease. RA has been shown to ameliorate podocyte injury through induction of expression of differentiation markers and regeneration of podocytes from its progenitor cells in animal models of kidney disease. The effects of RA in podocytes are mediated mainly by activation of the cAMP/PKA pathway via RA receptor-α (RARα) and activation of its downstream transcription factor, Kruppel-like factor 15. Screening of RA signaling molecules in human kidney disease has revealed RAR responder protein 1 (RARRES1) as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by high doses of both RA and TNF-α. Mechanistically, RARRES1 is cleaved by matrix metalloproteinases to generate soluble RARRES1, which then induces podocyte apoptosis through interaction with intracellular RIO kinase 1. Therefore, a high dose of RA may induce podocyte toxicity through upregulation of RARRES1. Based on the current findings, to avoid potential side effects, we propose three strategies to develop future therapies of RA for glomerular disease: 1) develop RARα- and Kruppel-like factor 15-specific agonists, 2) use the combination of a low dose of RAR-α agonist with phosphodiesterase 4 inhibitors, and 3) use a combination of RARα agonist with RARRES1 inhibitors.NEW & NOTEWORTHY Retinoic acid (RA) exerts pleotropic cellular effects, including induction of cell differentiation while inhibiting proliferation and inflammation. These effects are mediated by both RA responsive element-dependent or -independent pathways. In kidneys, RA confers renoprotection by signaling through podocyte RA receptor (RAR)α and activation of cAMP/PKA/Kruppel-like factor 15 pathway to promote podocyte differentiation. Nevertheless, in kidney disease settings, RA can also promote podocyte apoptosis and loss through downstream expression of RAR responder protein 1, a recently described risk factor for glomerular disease progression. These disparate roles of RA underscore the complexity of its effects in kidney homeostasis and disease, and a need to target specific RA-mediated pathways for effective therapeutic treatments against kidney disease progression.

Autocrine and paracrine effects of a novel podocyte gene, RARRES1.

Retinoic acid receptor responder protein 1 (RARRES1) has been identified as a novel gene for the regulation of podocyte function, and its expression is increased in glomerular disease and associated with disease progression. Increased expression of RARRES1 in podocytes leads to apoptosis through an autocrine effect. Möller-Hackbarth et al. recently found that RARRES1 expression is increased in the endothelial cells in some diseased kidneys to promote podocyte injury, likely through a paracrine effect.

Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy.

BACKGROUND: Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney diseases, HIV-associated nephropathy (HIVAN) is a rapidly progressive renal disease characterized by collapsing focal glomerulosclerosis (GS), microcystic tubular dilation, interstitial inflammation and fibrosis. Although the incidence of end-stage renal disease due to HIVAN has dramatically decreased with the widespread use of antiretroviral therapy, the prevalence of CKD continues to increase in HIV-positive individuals. Recent studies have highlighted the role of apoptosis signal-regulating kinase 1 (ASK1) in driving kidney disease progression through the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase and selective ASK-1 inhibitor GS-444217 was recently shown to reduce kidney injury and disease progression in various experimental models. Therefore we examined the efficacy of ASK1 antagonism by GS-444217 in the attenuation of HIVAN in Tg26 mice. METHODS: GS-444217-supplemented rodent chow was administered in Tg26 mice at 4 weeks of age when mild GS and proteinuria were already established. After 6 weeks of treatment, the kidney function assessment and histological analyses were performed and compared between age- and gender-matched control Tg26 and GS-444217-treated Tg26 mice. RESULTS: GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function. Taken together, GS-4442217 attenuated the full spectrum of HIVAN pathology in Tg26 mice. CONCLUSIONS: ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN.

The predictive value of diabetic retinopathy on subsequent diabetic nephropathy in patients with type 2 diabetes: a systematic review and meta-analysis of prospective studies.

This systematic review and meta-analysis aimed to assess the predictive value of diabetic retinopathy (DR) on further diabetic nephropathy (DN) risk in patients with type 2 diabetes (T2D) based on the prospective cohort studies. PubMed, Embase, and the Cochrane Library were systematically searched for eligible prospective cohort studies through March 2020. The predictive value of DR was assessed using sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) through the bivariate generalized linear mixed model and the random-effects model. Ten prospective cohort studies recruited 635 patients with T2D. The pooled sensitivity and specificity of DR for predicted DN were noted to be 0.64 (95% CI, 0.54-0.73) and 0.77 (95% CI, 0.60-0.88), respectively. The pooled PLR and NLR of DR for predicted DN were 2.72 (95% CI, 1.42-5.19) and 0.47 (95% CI, 0.33-0.67), respectively. The summary DOR for the relationship between DR and subsequent DN for T2D patients was 5.53 (95% CI, 2.00-15.30), and the AUC of DR for predicted DN was 0.73 (95% CI, 0.69-0.77). This study found significant associations between DR and subsequent DN risk for patients with T2D. Moreover, the predictive value of DR on subsequent DN risk was relatively lower.

Podocyte and endothelial-specific elimination of BAMBI identifies differential transforming growth factor-ß pathways contributing to diabetic glomerulopathy.

Transforming growth factor-ß (TGF-ß) is a central mediator of diabetic nephropathy. The effect of TGF-ß, mediated by the type I TGF-ß receptor, ALK5, and subsequent Smad2/3 activation results in podocyte apoptosis and loss. Previously, we demonstrated that the genetic deletion of the BMP and Activin Membrane-Bound Inhibitor (BAMBI), a negative modulator TGF-ß signaling, accelerates diabetic nephropathy in mice. This was associated with heightened ALK1-mediated activation of Smad1/5 in the glomerular endothelial cells (ECs). Therefore, to evaluate the glomerular cell-specific effects of TGF-ß in diabetic nephropathy we examined the effects of the podocyte- or EC-specific loss of Bambi (Pod-Bambi-/- or EC-Bambi-/-) in streptozotocin-induced diabetic mice with endothelial nitric oxide synthase deficiency. Interestingly, although hyperglycemia and body weight loss were similar in all groups of diabetic mice, significant hypertension was present only in the diabetic EC-Bambi-/- mice. While the podocyte or EC-specific loss of BAMBI both accelerated the progression of diabetic nephropathy, the worsened podocyte injury and loss observed in the diabetic Pod-Bambi-/- mice were associated with enhanced Smad3 activation. Increased Smad1/5 activation and EC proliferation were apparent only in the glomeruli of diabetic EC-Bambi-/- mice. The enhanced Smad1/5 activation in diabetic EC-Bambi-/- mice was associated with increased glomerular expression of plasmalemma vesicle-associated protein, pointing to the involvement of immature or dedifferentiated glomerular ECs in diabetic nephropathy. Notably, diabetic EC-Bambi-/- mice displayed podocyte injury and loss that were comparable to diabetic Pod-Bambi-/- mice. Thus, our results highlight the glomerular cell-specific contribution of TGF-ß signaling and the intricate cross-talk between injured glomerular cells in the progression of diabetic nephropathy.

Role of CD8+ T cells in crescentic glomerulonephritis.

Crescentic glomerulonephritis (cGN) comprises three main types according to the pathogenesis and immunofluorescence patterns: anti-glomerular basement membrane antibody cGN, vasculitis-associated cGN and post-infectious immune complex cGN. In this brief review of the immune-pathogenesis of cGN, the focus is mainly on the role of CD8+ T cells in the progression of cGN. Under control conditions, Bowman's capsule (BC) provides a protected immunological niche by preventing access of cytotoxic CD8+ T cells to Bowman's space and thereby podocytes. Even in experimental nephrotoxic nephritis, leukocytes accumulate around the glomeruli, but remain outside of BC, as long as the latter remains intact. However, when and where breaches in BC occur, the inflammatory cells can gain access to and destroy podocytes, thus converting cGN into rapidly progressive glomerulonephritis (RPGN). These conclusions also apply to human cGN, where biopsies show that loss of BC integrity is associated with RPGN and progression to end-stage kidney disease. We propose a two-hit hypothesis for the role of cytotoxic CD8+ T cells in the progression of cGN. The initial insult occurs in response to the immune complex formation or deposition, resulting in local capillary and podocyte injury (first hit). The injured podocytes release neo-epitopes, eventually causing T-cell activation and migration to the glomerulus. Upon generation of breaches in BC, macrophages and CD8+ T cells can now gain access to the glomerular space and destroy neo-epitope expressing podocytes (second hit), resulting in RPGN. While further investigation will be required to test this hypothesis, future therapeutic trials should consider targeting of CD8+ T cells in the therapy of progressive cGN.

Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor α.

Proliferation of glomerular epithelial cells, including podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum-induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wild-type mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wild-type mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wild-type mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to the coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells toward a podocyte phenotype. In vitro, RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.

Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study.

Objective: Emerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM). Methods: We used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results. Results: It was showed that Class Verrucomicrobiae [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,PFDR=0.0018], Order Verrucomicrobiales (OR=1.5651, 95%CI: 1.1810-2.0742, PFDR=0.0018) and Family Verrucomicrobiaceae (OR=1.3956, 95%CI:1.0336-1.8844, PFDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class Verrucomimicrobiae (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order Verrucomimicrobiae (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), Rhodospirillales (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family Verrucomicroniaceae (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The Eubacteriumprotogenes (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy. Conclusions: At the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.

Dietary sodium modulates mTORC1-dependent trained immunity in macrophages to accelerate CKD development.

Chronic Kidney Disease (CKD) is a significant global health issue linked to dietary habits, especially high salt intake. However, the precise mechanisms driving this progression remain incompletely understood. This study reveals that a high-salt diet intensifies macrophage trained immunity, leading to a marked pro-inflammatory response upon repeated pathogenic exposures, as evidenced by increased renal damage and fibrosis. Under high-salt conditions, there was an induction of CD45+F4/80+ macrophage infiltration into the renal tissue, accompanied by heightened production of inflammatory cytokines. Distinct responses were observed between circulating and resident renal macrophages to a high-salt diet, with a notable upsurge in the migration of pro-inflammatory macrophages, driven by CCL2-CCR2 signaling and aberrant mTORC1 pathway activation. Treatment with rapamycin-liposome effectively reduced this inflammatory cascade by mitigating mTORC1 signaling. Transplantation of monocytes from CKD mice with a high-salt diet significantly exacerbates renal inflammatory damage in the host mice, showing increased migratory tendency and inflammatory activity. The cell co-culture experiment further confirmed that macrophages derived from CKD mice, particularly those under conditions of high salt exposure, significantly induced apoptosis and inflammatory responses in renal tubular cells. Taken together, recurrent exposure to LPS elicits the activation of trained immunity, consequently augmenting inflammatory response of monocytes/macrophages in the involved kidneys. The high-salt diet exacerbates this phenomenon, attributable at least in part to the overactivation of the mTORC1 pathway. This research emphasizes the importance of dietary modulation and targeted immunological interventions in slowing CKD progression, providing new insights into mTORC1-mediated pathophysiological mechanisms and potential management strategies for CKD.

A potential defensive role of TIM-3 on T lymphocytes in the inflammatory involvement of diabetic kidney disease.

Objective: The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression. Methods: A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed. Results: Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened. Conclusion: Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.

Bowman's capsule rupture and the Oxford MEST-C score in adult patients with Immunoglobulin a vasculitis nephritis: a single center experience.

OBJECTIVE: Bowman's capsule rupture (BCR) is a glomerular pathological change, but it is still not well recognized in immunoglobulin A vasculitis nephritis (IgAV-N). The Oxford MEST-C score is a classification for IgA nephropathy; however, its clinical correlation and prognostic value in adult patients with IgAV-N are unclear. METHODS: A retrospective study of 145 adult patients with IgAV-N diagnosed by renal biopsy was conducted. Clinical manifestations, pathological changes and the prognosis of IgAV-N patients were compared depending on the presence or absence of BCR, International Study of Kidney Disease in Children (ISKDC) classification and MEST-C score. The primary endpoint events were end-stage renal disease, renal replacement therapy and all-cause death. RESULTS: In total, 51 of 145 (35.17%) patients with IgAV-N presented with BCR. Patients with BCR had more proteinuria, lower serum albumin, and more crescents. Compared with IgAV-N patients with crescents only, 51/100 patients with crescents combined with BCR had a higher proportion of crescents in all glomeruli (15.79% vs. 9.09%; p = 0.003). Patients with higher ISKDC grades had more severe clinical presentation, but it did not reflect the prognosis. However, the MEST-C score not only reflected clinical manifestations but also predicted prognosis (p < 0.05). BCR contributed to the effectiveness of the MEST-C score in predicting the prognosis of IgAV-N (C-index: 0.845 to 0.855). CONCLUSIONS: BCR is associated with clinical manifestations and pathological changes in patients with IgAV-N. The ISKDC classification and MEST-C score are related to the patient's condition, but only the MEST-C score is correlated with the prognosis of patients with IgAV-N, while BCR can improve its predictive ability.

BCR was associated with clinical manifestations and pathological changes in patients with IgAV-N, particularly crescents.The ISKDC classification was related to clinical manifestations of patients with IgAV-N, but it wasn't associated with prognosis.The Oxford MEST-C score was correlated to clinical presentations and prognosis of patients with IgAV-N, while BCR can improve its predictive ability.

Similarities and Differences between COVID-19-Associated Nephropathy and HIV-Associated Nephropathy.

Kidney disease is a major complication of viral infection, which can cause both acute and chronic kidney diseases via different mechanisms such as immune-mediated injury, kidney cell injury from a direct viral infection, systemic effects, and antiviral drug-induced nephrotoxicity. HIV-associated nephropathy (HIVAN), characterized by collapsing focal segmental glomerulosclerosis (cFSGS), has been described 2 decades ago as a major complication of acquired-immunodeficiency syndrome. The pathogenesis of HIVAN has been well studied, including viral entry, host response, and genetic factors. The incidence of this disease has been dramatically dropped with current antiretroviral therapy. In the recent severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic, acute kidney injury was also found to be a major complication in patients with (coronavirus disease) COVID-19. These patients also developed glomerular disease such as cFSGS in African Americans with apolipoprotein L1 risk alleles, similar to HIVAN. Whether SARS-CoV-2 can infect kidney cells locally remains controversial, but both local infection and systemic effects are likely involved in the pathogenesis of this disease. In this review, we present a comparison of the clinical presentations, pathological findings, disease mechanisms, and potential treatments between HIVAN and COVID-19. Leveraging the knowledge in HIVAN and experimental approaches used to study HIVAN will facilitate the exploration in the pathogenesis of COVID-19-associated kidney disease and improve our management of COVID-19 patients.

Inflammation in kidney repair: Mechanism and therapeutic potential.

The kidney has a remarkable ability of repair after acute kidney injury (AKI). However, when injury is severe or persistent, the repair is incomplete or maladaptive and may lead to chronic kidney disease (CKD). Maladaptive kidney repair involves multiple cell types and multifactorial processes, of which inflammation is a key component. In the process of inflammation, there is a bidirectional interplay between kidney parenchymal cells and the immune system. The extensive and complex crosstalk between renal tubular epithelial cells and interstitial cells, including immune cells, fibroblasts, and endothelial cells, governs the repair and recovery of the injured kidney. Further research in this field is imperative for the discovery of biomarkers and promising therapeutic targets for kidney repair. In this review, we summarize the latest progress in the immune response and inflammation during maladaptive kidney repair, analyzing the interaction between immune cells and intrinsic kidney cells, pointing out the potentialities of inflammation-related pathways as therapeutic targets, and discussing the challenges and future research prospects in this field.