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Age-dependent mitochondrial toxicity in renal stem cells: A precise 3D silk matrix model
Pengfei Yu1,2, Huifen Ding2, Jian-Xing Ma3
1The Fourth Department of Liver Disease, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
Abstract:
Aging is a significant risk factor for drug-induced kidney injury, underscoring the need for advanced preclinical models. The impact of age on the susceptibility of human primary kidney stem cells to drug-induced mitochondrial toxicity remains largely uncharacterized. To address this gap, we employed a well-established in vitro 3D model, utilizing a silk fiber matrix, to culture renal stem cells derived from both young and elderly donors. Tenofovir, a commonly prescribed antiretroviral medication linked to renal adverse effects, was used to investigate age-related drug-induced mitochondrial toxicity. Our findings reveal a pronounced age-dependent increase in tenofovir-induced mitochondrial dysfunction in older renal stem cells compared with their younger counterparts. This was characterized by diminished mitochondrial mass and function, ATP production, elevated oxidative stress, senescence gene expression, and compromised renal cell function. These results highlight the critical role of aging in exacerbating drug-induced renal injury. The 3D silk matrix model utilizing elderly donor-derived renal stem cells offers a promising platform for identifying medications with age-specific renal toxicity potential and for developing targeted therapies to safeguard the aging kidney.
Insights
Aging kidneys are more vulnerable to drug toxicity. Older kidney stem cells showed increased mitochondrial damage from tenofovir, highlighting aging
Area of Science:
- Nephrology
- Gerontology
- Pharmacology
Background:
- Aging is a major risk factor for drug-induced kidney injury.
- Preclinical models are needed to study age-related kidney toxicity.
- The effect of age on kidney stem cell susceptibility to mitochondrial toxicity is unknown.
Purpose of the Study:
- To investigate age-related differences in drug-induced mitochondrial toxicity in human renal stem cells.
- To characterize the impact of tenofovir on kidney stem cells from young and elderly donors.
- To evaluate a 3D silk matrix model for studying age-specific renal toxicity.
Main Methods:
- Cultured human renal stem cells from young and elderly donors in a 3D silk fiber matrix.
- Exposed cells to tenofovir, an antiretroviral drug.
- Assessed mitochondrial mass, function, ATP production, oxidative stress, senescence markers, and cell function.
Main Results:
- Older renal stem cells exhibited significantly higher tenofovir-induced mitochondrial dysfunction compared to younger cells.
- Diminished mitochondrial function, reduced ATP production, and increased oxidative stress were observed in aged cells.
- Elevated senescence gene expression and compromised renal cell function were noted in older stem cells.
Conclusions:
- Aging exacerbates drug-induced mitochondrial injury in renal stem cells.
- The 3D silk matrix model is effective for studying age-specific renal toxicity.
- This model can aid in identifying drugs with age-related kidney risks and developing protective therapies.
