Fyn Phosphorylates Transglutaminase 2 (Tgm2) and modulates autophagy and p53 expression in the development of diabetic kidney disease

Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophagy in proximal renal tubules both in vivo and in vitro. Phospho-proteomic analysis revealed that transglutaminase 2 (Tgm2), a protein involved in the degradation of p53 in the autophagosome, is phosphorylated on tyrosine 369 (Y369) by Fyn. Interestingly, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy in proximal renal tubules in vitro, and that p53 expression is decreased upon autophagy in Tgm2-knockdown proximal renal tubule cell models. Using streptozocin (STZ)-induced hyperglycemic mice, we confirmed that Fyn regulated autophagy and mediated p53 expression via Tgm2. Taken together, these data provide a molecular basis for the role of the Fyn–Tgm2–p53 axis in the development of DKD

Urinary Activin A: A Novel Biomarker for Human Acute Kidney Injury

Activin is a multifunctional cytokine belonging to the transforming growth factor (TGF)-β superfamily that regulates the growth and differentiation of cells in various organs. We previously reported that activin A, which is absent in normal kidneys, was significantly increased in the ischemic kidney, and that the blockade of activin action by follistatin, an activin antagonist, significantly enhanced tubular regeneration after renal ischemia, suggesting that activin A acts as an endogenous inhibitor of tubular repair after kidney injury in rodents. However, the role of activin A in human acute kidney injury (AKI) remains unclear. In this analysis, we measured serum and urinary activin A in human AKI (n = 39) and tested if activin A might serve as a biomarker for AKI. Urinary activin A, which was undetectable in healthy controls, was significantly increased in AKI (0.0 ± 0.0 vs. 173.4 ± 58.8 pg/mL, p < 0.05). The urinary activin A level in patients with AKI stage 3, was significantly higher than that in patients with AKI stages 1 and 2. Patients who required renal replacement therapy (RRT) had a significantly higher urinary activin A level than patients who did not require RRT. Urinary activin A might be a useful non-invasive biomarker for the severity of AKI

Diverse Cell Populations Involved in Regeneration of Renal Tubular Epithelium following Acute Kidney Injury

Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. Surviving tubular cells actively proliferate, migrate, and differentiate in the kidney regeneration process after injury, and some cells express putative stem cell markers or possess stem cell properties. Using fate mapping techniques, bone marrow-derived cells and endothelial progenitor cells have been shown to transdifferentiate into tubular components in vivo or ex vivo. Similarly, it has been demonstrated that, during tubular cell regeneration, several inflammatory cell populations migrate, assemble around tubular cells, and interact with tubular cells during the repair of tubular epithelium. In this review, we describe recent advances in understanding the regeneration mechanisms of renal tubules, particularly the characteristics of various cell populations contributing to tubular regeneration, and highlight the targets for the development of regenerative medicine for treating kidney diseases in humans

A Case of Castleman’s Disease with a Marked Infiltration of IgG4-Positive Cells in the Renal Interstitium

Multicentric Castleman’s disease (MCD) is a benign lymphoproliferative disorder with heterogenous clinical symptoms, and involves systemic organs in addition to lymph nodes. Herein, we present the case of a 55-year-old man with MCD characterized by an extensive infiltration of IgG4+ plasma cells in the kidneys. The patient presented to our hospital with a high fever and diarrhea. On admission, laboratory analysis revealed anemia, renal dysfunction (eGFR 30 mL/min/1.73 m2), polyclonal gammopathy (IgG 7130 mg/dL), elevated serum IgG4 level (2130 mg/dL), and increased C-reactive protein (8.0 mg/dL). An enlargement of lymph nodes in the axillary, mediastinal, para-aortic, and inguinal regions was observed on abdominal computed tomography. Axillary lymph node biopsy revealed interfollicular expansion due to dense plasma cell infiltration. Renal biopsy demonstrated significant plasma cell infiltration into the tubulointerstitium. Immunohistochemical analysis showed a 40% IgG4-positive/IgG-positive plasma cell ratio, meeting the diagnostic criteria for an IgG4-related disease. Amyloid A deposition was observed along vessel walls, and immunofluorescence analysis indicated granular positivity of IgG and C3 along the glomerular capillary wall. Elevated levels of interleukin-6 (21 pg/mL) and vascular endothelial growth factor (VEGF; 1210 pg/mL) were noted. Based on these findings, and the histological finding of the lymph node biopsy, idiopathic MCD was diagnosed. Corticosteroid monotherapy was only partially effective. Subsequently, tocilizumab administration was initiated, leading to sustained remission, even after discontinuation of prednisolone. Due to the diverse responses to steroid therapy and the varying prognoses observed in MCD and IgG4-related disease, it is essential to carefully diagnose MCD by thoroughly assessing the organ distribution of the disease, its response to steroid therapy, and any additional pathological findings