Cellular Senescence in Renal and Urinary Tract Disorders

Abstract

Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases.

Keywords: SASP; aging; chronic kidney disease; senescence; urogenital disorders.

Figure 1

Pathways involved in cell senescence. Senescence is induced by various stressors, which trigger DNA damage and subsequent activation of p53/p21 and p16/pRb pathways. p53 activation is achieved by phosphorylation by ATM/ATR and checkpoint kinases Chk1/Chk2. Likewise, p53 activity can be increased by binding of p14/P19^ARF product of the INK4a locus to MDM2 preventing degradation of p53. p53 can induce senescence by activating p21, which inhibits CDK2, leading to the hypophosphorylation of Rb. In addition to p53, the accumulation of the tumor-suppressor p16^INK4A also leads to cell cycle arrest through the inhibition of CDK4/CDK6 and subsequent hypophosphorylation of Rb. This enables Rb to bind to E2F, inhibiting cell cycle progression. ATM, ataxia-telangiectasia-mutated kinase; ATR, ataxia-telangiectasia- and ATM-Rad3-related kinase; MDM2, murine double minute 2; Rb, retinoblastoma.

Figure 2

Potential roles of senescent cells in renal and urinary tract disorders. Cellular senescence plays major but intricate roles in the progression of renal and urogenital disorders including kidney, prostate, and bladder dysfunction. While transient senescence appears to be beneficial in acute pathological conditions, chronic senescence hastens urogenital alterations. Senescent cell accumulation is linked to various deleterious conditions like kidney damage and fibrosis, transplant rejection, or benign prostate hyperplasia. Of particular importance, the release of pro-inflammatory and pro-fibrotic mediators by senescent cells is a powerful driver of tumor progression in the bladder and the prostate.