Division of Nephrology, University of Washington, Seattle, Washington, United States.
Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil.
Am J Physiol Renal Physiol. 2024 Jan 1;326(1):F120-F134. doi: 10.1152/ajprenal.00261.2023. Epub 2023 Oct 19.
As life expectancy continues to rise, age-related diseases are becoming more prevalent. For example, proteinuric glomerular diseases typified by podocyte injury have worse outcomes in the elderly compared with young patients. However, the reasons are not well understood. We hypothesized that injury to nonaged podocytes induces senescence, which in turn augments their aging processes. In primary cultured human podocytes, injury induced by a cytopathic antipodocyte antibody, adriamycin, or puromycin aminonucleoside increased the senescence-related genes (p16INK4a/p14ARF), (p19INK4d), and (p21). Podocyte injury in human kidney organoids was accompanied by increased expression of , , and In young mice, experimental focal segmental glomerulosclerosis (FSGS) induced by adriamycin and antipodocyte antibody increased the glomerular expression of p16, p21, and senescence-associated β-galactosidase (SA-β-gal). To assess the long-term effects of early podocyte injury-induced senescence, we temporally followed young mice with experimental FSGS through adulthood (12 m of age) and middle age (18 m of age). p16 and Sudan black staining were higher at middle age in mice with earlier FSGS compared with age-matched mice that did not get FSGS when young. This was accompanied by lower podocyte density, reduced canonical podocyte protein expression, and increased glomerular scarring. These results are consistent with injury-induced senescence in young podocytes, leading to increased senescence of podocytes by middle age accompanied by lower podocyte lifespan and health span. Glomerular function is decreased by aging. However, little is known about the molecular mechanisms involved in age-related glomerular changes and which factors could contribute to a worse glomerular aging process. Here, we reported that podocyte injury in young mice and culture podocytes induced senescence, a marker of aging, and accelerates glomerular aging when compared with healthy aging mice.
随着预期寿命的持续延长，与年龄相关的疾病变得更加普遍。例如，以足细胞损伤为特征的蛋白尿肾小球疾病在老年人中的预后比年轻患者更差。然而，其原因尚不清楚。我们假设，未老化的足细胞损伤会诱导衰老，进而加速其衰老过程。在原代培养的人足细胞中，细胞毒性抗足细胞抗体、阿霉素或嘌呤霉素氨基核苷诱导的损伤增加了衰老相关基因（p16INK4a/p14ARF）、（p19INK4d）和（p21）。人类肾类器官中的足细胞损伤伴随着 、 和 的表达增加。在年轻小鼠中，阿霉素和抗足细胞抗体诱导的实验性局灶节段性肾小球硬化（FSGS）增加了肾小球中 p16、p21 和衰老相关β-半乳糖苷酶（SA-β-gal）的表达。为了评估早期足细胞损伤诱导的衰老的长期影响，我们通过成年期（12 个月龄）和中年期（18 个月龄）对实验性 FSGS 的年轻小鼠进行了长期随访。与年轻时未发生 FSGS 的同龄小鼠相比，早期 FSGS 小鼠的肾小球中 p16 和苏丹黑染色在中年时更高。这伴随着足细胞密度降低、经典足细胞蛋白表达减少和肾小球瘢痕形成增加。这些结果与年轻足细胞损伤诱导的衰老一致，导致中年时足细胞衰老增加，同时足细胞寿命和健康寿命缩短。肾小球功能随年龄增长而下降。然而，关于与年龄相关的肾小球变化相关的分子机制以及哪些因素可能导致肾小球老化过程恶化知之甚少。在这里，我们报道了年轻小鼠的足细胞损伤和培养的足细胞诱导衰老，这是衰老的一个标志物，并加速了与健康衰老小鼠相比的肾小球衰老。
