Suppression of BRCA1 facilitates kidney regeneration

Acute kidney injury (AKI) is a medical condition characterized by a sudden decline in kidney function, driven by various risk factors, including old age, exposure to nephrotoxic drugs, major surgeries, and preexisting chronic kidney disease (CKD) (Ferenbach and Bonventre, 2015; Kellum et al., 2021). AKI has emerged as a global public health issue associated with significant morbidity and mortality. Although AKI survivors experience recovery of kidney structure and function, they remain at an elevated risk for developing progressive CKD, kidney fibrosis, proteinuria, and cardiovascular complications (Kellum et al., 2021). Additionally, therapeutic interventions for AKI have been proven ineffective in clinical settings, resulting in limited supportive treatment options (Kher et al., 2017).

In AKI, direct damage to heterogeneous tubular epithelial cells can cause injury to some nephrons, while neighboring nephrons remain unaffected. Surviving tubular cells possess the capacity to regenerate and initiate a repair response that can be either adaptive or maladaptive (Ferenbach and Bonventre, 2015). In adaptive repair, a strong proliferative response, particularly in the proximal tubules, leads to full restoration of the normal epithelium, allowing for complete recovery of renal function. However, in cases of severe or repetitive injury, maladaptive repair dominates resulting in profibrogenic inflammation, cellular senescence, upregulation of proinflammatory signaling pathway, and cell cycle arrest (Ferenbach and Bonventre, 2015; Lee and Kalluri, 2010). Maladaptive repair is primarily attributed to cell cycle arrest in the G2/M phase, where damaged tubular epithelium cells fail to complete the regenerative process, leading to incomplete structural and functional deterioration of the kidney (Yang et al., 2010).

Cell cycle arrest is generally beneficial, as it allows cells time to repair DNA before resuming proliferation. However, rapid progression through cell cycle phases without proper checkpoints or prolonged arrest can result in DNA damage, leading to a series of pathological changes that impair tubular function. When cell cycle arrest becomes permanent, or cells undergo repeated proliferation during the chronic transition from AKI to CKD, telomere shortening may occur, contributing to cellular senescence and further complicating the repair process, thus accelerating the development of CKD (Canaud and Bonventre, 2015). Senescent cells are metabolically active, resistant to apoptosis, and can trigger the “senescence-associated secretory phenotype” (Chen et al., 2024). During the AKI to CKD transition, senescent cells, particularly in the proximal tubular epithelium, secrete proinflammatory cytokines and profibrotic factors, creating a detrimental microenvironment. The microenvironment of this transition phase is characterized by the release of proinflammatory cytokines, including IL-1β, IL-6, and IL-8, as well as profibrotic TGF-β1, influencing the behavior of neighboring cells and promoting a pro-CKD environment (Xu et al., 2020).

Typically, when senescent cells enter a state of permanent cell cycle arrest, their ability to proliferate is impaired, ultimately promoting the progression of kidney damage. Cyclin-dependent kinase (CDK) inhibitors, such as p16^Ink4a and/or p21^Cip1, are crucial for the induction of senescence. p16^Ink4a primarily downregulates CDK4 and CDK6 during cell senescence, while p21 enforces a G1 phase blockade in response to DNA damage, leading to the formation of senescence-associated heterochromatin foci, which reflects the altered DNA packaging within senescent cells (Huang et al., 2022). Senescent cells can also generate numerous anti-apoptotic molecules, such as Bcl-2, Bcl-w, and Bcl-xL, accompanied by the activation of multiple signaling cascades, such as Bcl-2/Bcl-xL, p53/p21, and PI3K/AKT pathways, which protect senescent cells from immune surveillance and contribute to their resistance to apoptosis (Chen et al., 2024).

Breast cancer susceptibility gene 1 (BRCA1), a well-known tumor suppressor, plays a critical role in maintaining genomic integrity by facilitating the repair of DNA double-strand breaks through homologous recombination (Venkitaraman, 2014). BRCA1 forms a complex with RAD51, a key protein aiding in the precise repair of DNA double-strand breaks via homologous recombination (Cousineau et al., 2005). In the current issue of JEM, Ajay et al. report the noncancerous role of BRCA1 in maladaptive repair after kidney injury, wherein BRCA1 levels were upregulated in the cytoplasm and nuclei of human CKD kidneys with increased levels of DNA damage marker p16^Ink4a and GATA4 (Ajay et al., 2025) (see first figure). Utilizing a genetic approach to conditionally delete Brca1 in proximal tubule epithelial cells (PTCs), Brca1 deletion resulted in reduced interstitial fibrosis, decreased tubular atrophy, and lower myofibroblast activation in Brca1^{Δ11flox/Δ11flox} and Slc34a1-Cre^ERT2 mice, compared with wild-type mice in bilateral ischemia reperfusion and aristolochic acid (AA)–induced kidney fibrosis models (see first figure).

Sophisticated cell fate tracing analyses revealed that targeted Brca1 deletion also resulted in S phase–processed BrdU⁺Ki67⁺ epithelial cells undergoing apoptosis following tubular injury. This upregulation in cellular apoptosis was correlated with a reduction in tubular senescence, shown by lower expression of senescence markers SA-β-Gal, p16^INK4a, and GATA4, and decreased nuclear RAD51 levels in Brca1 deletion mice (see first figure). These findings indicate that loss of Brca1 disrupts normal cell cycle progression and DNA repair processes, leading to cell cycle arrest at the G1/S phase and fewer cells in the G2/M phase. Consequently, this disruption causes PTCs to halt proliferation and undergo apoptosis instead of engaging in maladaptive repair and senescence.

Ajay et al. (2025) validated these in vivo findings using patient-derived PTCs and human PTC cell lines treated with AA (see second figure). AA treatment in patient-derived PTCs resulted in an upregulation in pBRCA1^S1524 expression and increased p53 and p21 at the protein and RNA levels (see second figure). Leveraging the genetic manipulation responsiveness of HK2 and HKC8 human kidney epithelial cells, treatment with Brca1-targeting siRNAs reduced BrdU⁺ S phase cells, as well as pH3 and GATA4 senescence markers (see second figure). To investigate paracrine signaling of epithelial cell–derived BRCA1 in fibrotic response, the pericyte cell line 10T1/2 was incubated with conditioned medium from Brca1-targeting siRNAs transfected HKC8 cells treated with AA (see second figure). Treatment with conditioned medium from BRCA1 knockdown HKC8 cells incubated with AA resulted in a reduction in profibrotic factors at the mRNA level and fibronectin and α-SMA expression at the protein level (see second figure).

In conclusion, while BRCA1 is widely recognized for its critical function in DNA repair and cancer suppression, this study provides novel mechanistic insights on the role of BRCA1 in regulating DNA repair and opens new avenues for exploring BRCA1’s noncancerous roles in maladaptive repair following kidney injury. It also highlights the complexity of tumor suppressor genes, which can exhibit protective roles in cancer while potentially contributing to detrimental outcomes in kidney fibrosis. Moving forward, further investigations into how BRCA1 regulates tissue remodeling and other fibrotic diseases or chronic disorders could inform novel treatment strategies.