LAUSR

Cellular senescence, defined as the irreversible cell cycle arrest, plays an important role in both development and disease. While acute senescence is important for organogenesis and proper wound healing, perpetuation of the senescent population is associated with extensive transcriptomic reprogramming. The accompanying metabolic changes and acquisition of inflammatory and secretory properties by chronically senescent cells lead to abnormal organ repair, matrix accumulation and tissue fibrosis. Permanently growth-arrested, phenotypically-altered senescent renal cells are evident in various renal injuries (e.g., ischemic, obstructive, toxin-induced, diabetic and hypertensive) and accumulate in the kidney with increasing age where they are associated with progressive scarring, declining organ function and reduced regenerative capacity. Acute kidney injury (AKI) is a common and frequently life-threatening condition that often progresses to fibrosis and chronic stage disease (CKD). CKD patients, moreover, are more susceptible to AKI as are aging adults and CKDprevalence is significantly higher in older individuals. Although cellular senescence is an important contributor to progressive fibrosis, the underlying mechanisms are not well understood. Furthermore, renal aging and CKD share certain pathophysiologic features suggesting a mechanistic linkage between the two processes. The papers in this Special Issue entitled “Premature Aging and Senescence in Renal Fibrosis” probe the biological basis of this interrelationship. This collection addresses the molecular and pathologic underpinnings of renal aging and the senescent phenotype that contribute to renal injury, failed or maladaptive repair and progressive fibrosis and build on the literature highlighting the role of age-dependent pathology on kidney disease (Kanasaki et al., 2012; Ruiz-Ortega et al., 2020; Mylonas et al., 2021). The elegant review byXu et al draws parallels among renal aging, senescence, andCKDprogression. The senescence-associated secretory phenotype (SASP), characterized by increased production of inflammatory mediators, matrix modulators and cytokines, orchestrates pathogenic cell-cell communications in the renal parenchyma with predisposition to fibrosis. Targeting the SASP, therefore, is a potentially viable strategy to attenuate fibrosis. Rescue of endogenous inhibitors of senescence such as the anti-aging protein klotho, which is known to be repressed in many nephropathies regardless of etiology, provides another avenue to mitigate fibrosis and the transition to CKD. The recognition that several renal cell types including tubular and endothelial elements as well as interstitial fibroblasts acquire senescent characteristics in aging and disease suggests there may be multiple targets for senotherapy. Docherty et al draw distinctions between normal and senescent cells in another state-of-the-art review published in this issue. They discuss role of cellular senescence during development as well as in several pathological settings and describe the beneficial impact of acute senescence and the detrimental effects of chronic senescence and SASP in progressive renal disease. Depletion of senescent cells in the kidney, via transgenic as well as pharmacological strategies, attenuates fibrogenesis and improves renal function. Senostatic approaches that target SASP also mitigate CKD progression. Edited and reviewed by: Giuseppe Remuzzi, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Italy