5 research outputs found
Protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes.
To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5-/-) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5-/- mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5-/- mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5-/- mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy
Establishment of a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury
Renal artery stenosis-induced chronic renal ischemia is an important cause of renal dysfunction, especially in older adults, and its incidence is currently increasing. To elucidate the mechanisms underlying chronic renal hypoperfusion-induced kidney damage, we developed a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury. This model exhibits decreased renal blood flow and function, atrophy, and parenchymal injury in the coiled kidney, along with compensatory hypertrophy in the non-coiled kidney, without chronic hypertension. The availability of this mouse model, which can develop renal ischemia without genetic modification, will enhance kidney disease research by serving as a new tool to investigate the effects of acquired factors (e.g., obesity and aging) and genetic factors on renal artery stenosis-related renal parenchymal damage
A Long-term Estimated Glomerular Filtration Rate Plot Analysis Permits the Accurate Assessment of a Decline in the Renal Function by Minimizing the Influence of Estimated Glomerular Filtration Rate Fluctuations.
Objective:Evaluating the rate of decline in the estimated glomerular filtration rate (eGFR) may help identify patients with occult chronic kidney disease (CKD). We herein report that eGFR fluctuation complicates the assessment of the rate of decline and propose a long-term eGFR plot analysis as a solution.Methods:In 142 patients with persistent eGFR decline in a single hospital, we evaluated the factors influencing the rate of eGFR decline, calculated over the long term (≥3 years) and short term (<3 years) using eGFR plots, taking into account eGFR fluctuation between visits.Results:The difference between the rate of eGFR decline calculated using short- and long-term plots increased as the time period considered in the short-term plots became shorter. A regression analysis revealed that eGFR fluctuation was the only factor that explained the difference and that the fluctuation exceeded the annual eGFR decline in all participants. Furthermore, the larger the eGFR fluctuation, the more difficult it became to detect eGFR decline using a short-term eGFR analysis. Obesity, a high eGFR at baseline, and faster eGFR decline were associated with larger eGFR fluctuations. To circumvent the issue of eGFR fluctuation in the assessment of the rate of eGFR decline, we developed a system that generates a long-term eGFR plot using all eGFR values for a participant, which enabled the detection of occult CKD, facilitating early therapeutic intervention.Conclusion:The construction of long-term eGFR plots is useful for identifying patients with progressive eGFR decline, as it minimizes the effect of eGFR fluctuation