At the convergence point of multiple cytokine signals, signal transducer and activator of transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, a natural small‐molecule inhibitor of STAT3, may have beneficial effects on diabetic nephropathy; however, the underlying mechanism remains unclear. Isoquercitrin significantly mitigated renal inflammation and fibrosis by inhibiting STAT3 activity in mice with diabetic nephropathy. Moreover, STAT3 is a direct molecular target of isoquercitrin, which as corroborated by tight and stable noncovalent binding between them. This interaction is mechanistically supported by the affinity of isoquercitrin for the Ser668–Gln635–Gln633 region within the pY+1 binding pocket of the SH2 domain. This binding obstructs pivotal processes like STAT3 phosphorylation and dimerization, thereby suppressing its transcriptional function. Finally, a kidney‐targeted nanocarrier, Iso@PEG‐GK, is developed to load isoquercitrin, thus enhancing its therapeutic precision for diabetic nephropathy. Iso@PEG‐GK significantly improved the absorption and renal distribution of isoquercitrin. This study is the first to demonstrate that isoquercitrin exerts a significant protective effect against diabetic nephropathy and may provide a novel therapeutic drug for this disease.

IgA nephropathy (IgAN) is one of the most common primary glomerular diseases worldwide, but effective therapy remains limited and many patients progress to end-stage renal disease (ESRD). Only angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin-receptor blockers (ARB) show a high level of evidence (1B level) of being of value in the treatment for IgAN according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. However, traditional Chinese medicine has raised attention in kidney disease research. Abelmoschus manihot, a single medicament of traditional Chinese medicine has shown therapeutic effects in primary glomerular disease according to the randomized controlled clinical trial that we have completed. Here, we conduct a new study to assess the efficacy and safety of Abelmoschus manihot in IgAN. Also, this study is currently the largest double-blind, randomized controlled registered clinical research for the treatment of IgAN. We will conduct a multicenter, prospective, double-blind, double-dummy randomized controlled study. The study is designed as a noninferiority clinical trial. Approximately 1600 biopsy-proven IgAN patients will be enrolled at 100 centers in China and followed up for as long as 48 weeks. IgAN patients will be randomized assigned to the Abelmoschus manihot group (in the form of a huangkui capsule, 2.5 g, three times per day) and the losartan potassium group (losartan potassium, 100 mg/d). The primary outcome is the change in 24-h proteinuria from baseline after 48 weeks of treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after 48 weeks of treatment, the incidence of endpoint events (proteinuria ≥3.5 g/24 h, the doubling of serum creatinine, or receiving blood purification treatment) are the secondary outcomes. Twenty-four-hour proteinuria and eGFR are measured at 0, 4, 12, 24, 36 and 48 weeks. This study will be of sufficient size and scope to evaluate the efficacy and safety of Abelmoschus manihot compared to losartan potassium in treating patients with IgAN. The results of this study may provide a new, effective and safe treatment strategy for IgAN. ClinicalTrials.gov, identifier: NCT02231125 . Registered on 30 August 2014.

Abelmoschus manihot (A.manihot) is a herbaceous flowering medicinal plant and flavonoids are its main pharmacological active ingredients. A.manihot is listed in the 2020 edition of the Chinese Pharmacopoeia for the treatment of chronic kidney disease (CKD). A.manihot significantly reduces proteinuria in CKD, and the effectiveness and safety of A.manihot in the treatment including primary glomerulonephropathy and diabetic kidney disease (DKD) have been proved by several randomized controlled trials (RCT). Emerging pharmacological studies have explored the potential active small molecules and the underlying mechanisms in A.manihot. The active constituents of A.manihot are mainly seven flavonoids, including hibifolin, hyperoside, isoquercetin, rutin, quercetin, myricetin, and quercetin-3-O-robinobioside. The mechanisms of action mainly include alleviating renal fibrosis, reducing the inflammatory response and decreasing the apoptosis of podocytes. In this review, we summarize the updated information of active components and molecular mechanisms of A.manihot on chronic kidney disease.

Renal fibrosis-characterized by microcirculatory disturbances and endothelial-mesenchymal transition (EndMT)-is a major pathological feature of chronic kidney disease (CKD) and remains a significant therapeutic challenge. The mechanosensitive ion channel Piezo1 plays a pivotal role in endothelial mechanotransduction and has been implicated in fibrogenesis, yet specific pharmacological interventions targeting Piezo1 are lacking. We evaluated the renoprotective effects of paeoniflorin (PF), a bioactive monoterpene glycoside, in 5/6 nephrectomy-induced chronic renal failure (CRF) rats and diabetic kidney disease (DKD) db/db mice. PF-Piezo1 interactions were characterized using molecular docking, surface plasmon resonance (SPR), and functional assays. In vitro studies employing models of matrix stiffness, endothelial-fibroblast crosstalk, and HIF-1α inhibition were performed to elucidate the underlying mechanisms. PF treatment preserved renal function, reduced glomerulosclerosis, and ameliorated microvascular rarefaction in both CRF and DKD. Molecular docking and SPR analyses revealed that PF binds Piezo1 with high affinity, thereby inhibiting Yoda1-induced Ca2⁺ influx and attenuating stiffness-induced EndMT. PF restored the expression of endothelial markers including VE-cadherin and eNOS, and suppressed HIF-1α-mediated upregulation of Vimentin and TGF-β1. Moreover, co-culture experiments demonstrated that PF disrupted endothelial-derived TGF-β1 paracrine signaling, reducing fibroblast activation and extracellular matrix deposition. Notably, Piezo1 knockdown or HIF-1α inhibition recapitulated the dual effects of PF on endothelial restoration and fibrosis suppression. Our findings indicate that PF exerts renoprotective effects by targeting the Piezo1/Ca²⁺/HIF-1α axis, thereby mitigating renal fibrosis. By interrupting pathological endothelial-fibroblast communication and restoring microvascular integrity, PF represents a promising mechanotherapeutic strategy for CKD.

Aim: We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease patients.Methods: Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and 12 common events. Efficacy was mainly analyzed with hemoglobin response. All reported results were summarized using mean difference and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots.Results: Twenty trials (19 studies) with 14,947 participants were included, comparing six HIF-PHIs with erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in overall AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in enarodustat and roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52–31.40, p = 0.01; RR: 1.30, 95% CI: 1.04–1.61, p = 0.02). The occurrence of hypertension was lower in vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69–0.96, p = 0.01). The occurrence of vascular-access complications was higher in roxadustat (RR: 1.15, 95% CI: 1.04–1.27, p<0.01) and lower in daprodustat (RR: 0.78, 95% CI: 0.66–0.92, p<0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For hemoglobin response, network meta-analysis showed that compared with ESAs, significant increases were shown in roxadustat (RR: 1.04, 95% CI: 1.01–1.07, p<0.01) and desidustat (RR: 1.22, 95% CI: 1.01–1.48, p = 0.04), whereas noticeable reductions were indicated in vadadustat (RR: 0.88, 95% CI: 0.82–0.94, p<0.01) and molidustat (RR: 0.83, 95% CI: 0.70–0.98, p = 0.02). There was no significant difference between daprodustat and ESAs (RR: 0.97, 95% CI: 0.89–1.06, p = 0.47).Conclusion: Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision making.Systematic review registration: This study is registered with PROSPERO (registration number CRD42022312252)

A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.