Macrophage iron dyshomeostasis promotes aging-related renal fibrosis.

Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular cells during aging. Suppressing ferroptosis alleviates macrophage-mediated tubular partial epithelial-mesenchymal transition in vitro, thereby mitigating the expression of fibrosis-related genes. Using SCENIC analysis, we infer Stat1 as a key age-related transcription factor promoting iron dyshomeostasis and ferroptosis in macrophages by regulating the expression of Pcbp1, an iron chaperone protein that inhibits ferroptosis. Furthermore, through virtual screening and molecular docking from a library of anti-aging compounds, we construct a docking model targeting Pcbp1, which indicates that the natural small molecule compound Rutin can suppress macrophage senescence and ferroptosis by preserving Pcbp1. In summary, our study underscores the crucial role of macrophage iron dyshomeostasis and ferroptosis in renal aging. Our results also suggest Pcbp1 as an intervention target in aging-related renal fibrosis and highlight Rutin as a potential therapeutic agent in mitigating age-related renal chronic low-grade inflammation and fibrosis.

Sofosbuvir and ledipasvir decreased nephrotic syndrome caused by IgA nephropathy with a membranoproliferative pattern of injury in hepatitis C virus-induced cirrhosis: a case report.

Background: Immunoglobulin (Ig) A nephropathy (IgAN) with a membranoproliferative pattern of injury that manifests as nephrotic syndrome (NS) is rarely reported in hepatitis C virus (HCV)-induced cirrhosis. It is not known whether eradication of HCV by direct-acting antiviral (DAA) drugs can lead to remission of proteinuria and improve the long-term prognosis. Case Description: We report the case of a 52-year-old woman with HCV cirrhosis for 10 years. She had undergone splenectomy and cholecystectomy due to complications of liver cirrhosis. The patient presented with NS and was diagnosed by kidney biopsy with IgAN with a membranoproliferative pattern of injury. Twelve-week sofosbuvir and ledipasvir therapy successfully eradicated HCV in this decompensated cirrhosis patient and resulted in partial remission of IgAN. The patient stayed in partial remission for 4 years and had her first relapse with deterioration of portal hypertension and suspected hepatic carcinoma despite a sustained HCV virologic response. We consider the IgAN in this case to be secondary to liver cirrhosis and HCV infection rather than a primary nephropathy. DAA drugs which have no direct reno-protective effect resulted in partial remission of IgAN because they eradicated HCV and improved the liver disorder. Conclusions: Although relapse of IgAN could occur when liver cirrhosis deteriorates, DAA treatment may be considered an alternative for similar patients.

A retrospective cohort study on the pathology and outcomes of type 2 diabetic patients with renal involvement.

OBJECTIVE: To investigate the association of clinical and histological characteristics and the development of ESRD in T2DM patients with renal involvement. METHODS: We conducted a retrospective analysis of clinical and pathologic data from T2DM patients who underwent renal biopsy (n = 120). RESULTS: The mean age, duration of diabetes, and eGFR were 50.9 ± 11.2 years, 92.8 ± 41.3 months, 55.1 ± 42.3 mL/min/1.73 m2, respectively. Among these patients, 57 (47.5%) were diagnosed with diabetic nephropathy (DN), and 63 (52.5%) with non-diabetic renal disease (NDRD). The most common subtype of NDRD is membranous nephropathy. Compared with the NDRD group, the DN group had a longer duration of diabetes, worse renal function, and a higher proportion of diabetic retinopathy. Kaplan-Meier analysis showed that the 5-year renal survival rate of the DN group was only 41%, whereas that of the NDRD group was 84%. ESRD was defined as eGFR below 15 mL/min/1.73 m2. After multivariate adjustment, the risk of ESRD in DN patients was 3.81 times higher than that in NDRD patients. According to Glomerular Class, the 5-year renal survival rate of type IIA, IIB, III, and IV in the DN group was 88, 56, 28, and 15%, respectively. Kaplan-Meier analysis showed that there was a significant difference in renal survival among different glomerular classes or different interstitial fibrosis and tubular atrophy (IFTA) scores. But Cox proportional hazards analysis indicated that only IFTA score (HR 2.75, 95% CI 1.37-5.51, P = 0.001), but not the glomerular class (HR 1.21, 95% CI 0.73-2.00, P = 0.465), could predict renal outcome when adjusting for multivariate. CONCLUSION: The prognosis of DN patients is significantly worse than that of NDRD patients. Compared with glomerular lesions, tubulointerstitial lesions were associated with higher risk for renal death in DN patients.

Activation of Sirtuin 3 by Silybin Attenuates Mitochondrial Dysfunction in Cisplatin-induced Acute Kidney Injury.

Silybin is a secondary metabolite isolated from the seeds of blessed milk thistle (Silybum marianum) that has anti-inflammatory, antioxidative, antifibrotic, and antitumor properties. Here, we showed that silybin protected against cisplatin-induced acute kidney injury (AKI) by improving mitochondrial function through the regulation of sirtuin 3 (SIRT3) expression. Male SV129 and SIRT3 knockout (KO) mice were administered a single intraperitoneal (i.p.) injection of cisplatin with or without treatment with silybin. Moreover, cultured HK2 cells were used to evaluate mitochondrial morphology and function. Our data suggested that silybin enhanced SIRT3 expression after cisplatin administration both in vivo and in vitro. Silybin treatment improved mitochondrial function and bioenergetics in wild-type, but not SIRT3-defective, cells and mice. Moreover, we demonstrated that silybin markedly attenuated cisplatin-induced AKI and tubular cell apoptosis and improved cell regeneration in a SIRT3-dependent manner. Collectively, these results suggest that silybin is a pharmacological activator of SIRT3 capable of protecting against cisplatin-induced tubular cell apoptosis and AKI by improving mitochondrial function. Thus, silybin could serve as a potential clinical renoprotective adjuvant treatment in cisplatin chemotherapy.