Tetrandrine Attenuates Podocyte Injury by Inhibiting TRPC6-Mediated RhoA/ROCK1 Pathway.

Tetrandrine (Tet), a compound found in a traditional Chinese medicine, presents the protective effect for kidney function. Our study is aimed at clarifying the efficacy and underlying mechanism of Tet on podocyte injury. In this study, podocyte injury was induced in rats with adriamycin (ADR), and MPC5 podocytes were constructed with TRPC6 overexpression. We found that Tet treatment reduced the levels of proteinuria, serum creatinine, and blood urea nitrogen and increased plasma albumin levels in ADR-induced rats. Tet reduced intracellular Ca2+ influx and apoptosis in MPC5 podocytes overexpressing TRPC6. Tet downregulated the expression of renal TRPC6, RhoA, and ROCK1 and upregulated the expression of synaptopodin; meanwhile, it reduced calcineurin activity in vivo and in vitro. In conclusion, Tet protects against podocyte by affecting TRPC6 and its downstream RhoA/ROCK1 signaling pathway.

Network Pharmacology and In Vivo Experimental Validation to Uncover the Renoprotective Mechanisms of Fangji Huangqi Decoction on Nephrotic Syndrome.

Background: Fangji Huangqi decoction (FHD) is a traditional Chinese medicine formula that has the potential efficacy for nephrotic syndrome (NS) treatment. This study aims to explore the effects and underlying mechanisms of FHD against NS via network pharmacology and in vivo experiments. Methods: The bioactive compounds and targets of FHD were retrieved from the TCMSP database. NS-related targets were collected from GeneCards and DisGeNET databases. The compound-target and protein-protein interaction networks were constructed by Cytoscape 3.8 and BisoGenet, respectively. GO and KEGG analyses were performed by the DAVID online tool. The interactions between active compounds and hub genes were revealed by molecular docking. An NS rat model was established to validate the renoprotective effects and molecular mechanisms of FHD against NS in vivo. Results: A total of 32 hub genes were predicted to play essential roles in FHD treating NS. Eight main bioactive compounds of FHD had the good affinity with 9 hub targets (CCL2, IL-10, PTGS2, TNF, MAPK1, IL-6, CXCL8, TP53, and VEGFA). The therapeutic effect of FHD on NS was closely involved in the regulation of inflammation and PI3K-Akt pathway. In vivo experiments confirmed the renoprotective effect of FHD on NS, evidenced by reducing the levels of proteinuria, serum creatinine, blood urea nitrogen, and inflammatory factors in NS rats. The PI3K activator 740Y-P weakened the effects of FHD against NS. Furthermore, FHD downregulated the levels of PTGS2, MAPK1, IL-6, and p-Akt in NS rats. Conclusions: FHD alleviates kidney injury and inflammation in NS by targeting PTGS2, MAPK1, IL-6, and PI3K-Akt pathway.

Mechanochemical prepared ibuprofen-Polygonatum sibiricum polysaccharide drug delivery system for enhanced bioactivity with reduced renal injury induced by NSAIDs.

Ibuprofen (IBU) was a widely used NSAID (a type of nonsteroidal anti-inflammatory drug) worldwide, and many drug deliveries had been reported to enhance bioavailability. However, higher bioavailability would increase the danger of renal injury caused by oxidative stress. This study prepared IBU-Polygonatum sibiricum polysaccharide (IBU-PSP) drug delivery system via mechanochemical method. Due to drug delivery and renal protection effect of Polygonatum sibiricum polysaccharide (PSP), the solubility of IBU-PSP was increased 8.22 times, and the bioavailability was increased 2.52 times compared with IBU, carrageenin-induced rat paw edema test also increased. Meanwhile, short-term and long-term renal injuries induced by IBU were notable decreases. In conclusion, IBU-PSP was a multifunctional drug delivery system with superior anti-inflammatory and renal protection effects. It will benefit from developing high-efficiency NADIs preparations with safer clinical applications while providing an efficient and energy-saving technology for polysaccharide drug delivery.

Uric Acid as a Predictor of Immunoglobulin A Nephropathy Progression: A Cohort Study of 1965 Cases.

BACKGROUND: The role of serum uric acid (SUA) level in the progression of Immunoglobulin A nephropathy (IgAN) remains controversial. METHODS: In a cohort of 1,965 cases with biopsy-proven IgAN, we examined the associations of SUA concentration with the primary outcome of a composite of all-cause mortality or kidney failure (defined as a reduction of estimated glomerular filtration rate [eGFR] by 40% from baseline, requirements for dialysis and transplantation), or the outcome of kidney failure alone, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. RESULTS: At baseline, the mean age was 33.37 ± 11.07 years, eGFR was 101.30 ± 30.49 mL/min/1.73 m2, and mean uric acid level was 5.32 ± 1.76 mg/dL. During a median of 7-year follow-up, 317 cases reached the composite outcome of all-cause mortality (5 deaths) or kidney failure (36 cases of dialysis, 5 cases of renal transplantation, and 271 cases with reduction of eGFR by 40% from baseline). After adjustment for demographic and IgAN specific covariates and treatments, a higher quartile of uric acid was linearly associated with an increased risk of the primary outcome (highest versus lowest quartile, hazard ratio [HR] 2.39; 95% CI 1.52-3.75) and kidney failure (highest versus lowest quartile, HR 2.55; 95% CI 1.62-4.01) in the Cox proportional hazards regression models. In the continuous analysis, a 1 mg/dL greater uric acid level was associated with 16% increased risk of primary outcome (HR 1.16, 95% CI 1.07-1.25) and 17% increased risk of kidney failure (HR 1.17, 95% CI 1.08-1.27), respectively, in the fully adjusted model. The multivariate -logistic regression analyses for the sensitive analyses drew consistent results. In the subgroup analyses, significant interactions were detected that patients with mean arterial pressure (MAP) < 90 mm Hg or mesangial hypercellularity had a higher association of SUA with the incidence of the primary outcome than those with MAP ≥90 mm Hg or those without mesangial hypercellularity respectively. Hyperuricemia was not significantly associated with the risk of developing the primary outcome in elder patients (≥32 years old), patients with eGFR < 90 mL/min or with tubular atrophy/interstitial fibrosis. CONCLUSIONS: SUA level may be positively associated with the progression of IgAN. It was noticeable that the association of hyperuricemia with IgAN progression was less significant in patients with elder age, lower eGFR, or tubular atrophy/interstitial fibrosis, which may be due to some more confounders in association with the IgA progression in these patients. Future prospective studies are warranted to confirm these findings and to investigate the underlying mechanisms.