PRDM16 Attenuates Glomerular Aging by Upregulating Autophagy of Podocytes

Background: Aging leads to age-related glomerulosclerosis and a decline in GFR, manifested by the loss and reduced density of podocytes. As terminally differentiated cells, podocytes have high autophagic activity to maintain cellular homeostasis. Reduced autophagy in podocytes results in their damage and accelerates aging. Previous research by our group found that PR domain-containing 16 (PRDM16) expression decreases in damaged podocytes; however, the role of PRDM16 in podocyte aging and its relationship with autophagy levels remain unclear. Methods: We investigated the function and mechanism of PRDM16 in natural aging animal models and immortalized human podocytes cell line models to provide a theoretical basis for targeted delay of podocyte aging. The mouse models included 24-month-old wild-type mice with PRDM16 lenti-virus injected into the renal cortexand and naturally aging mice withSelective knockout of PRDM16 in podocytes(PRDM16Flox/NPHS2 Cre) mice , supplemented by various morphological and molecular biology tests. The cellular model used an immortalized human podocyte line treated with adriamycin and X-ray irradiation, supplemented by various morphological and molecular biology tests, to confirm that PRDM16 regulates autophagy levels and thereby affects podocyte aging. Results: In aged mice kidney , podocyte damage and sclerosis worsen, and PRDM16 expression decreases in podocytes. In podocytes aged by adriamycin or X-ray irradiation, both transcription and translation levels of PRDM16 are reduced. In vivo, localized overexpression of PRDM16 in the renal cortex significantly reduces proteinuria levels in aged mice, improves autophagic flux, and protects podocyte function. Conversely,Specific knockdown of PRDM16 in podocytes in vivo further reduces autophagy and exacerbates podocyte damage, sclerosis, and aging in elderly mice. In vitro, overexpression of PRDM16 effectively restores autophagic flux stimulated by radiotherapy and alleviates podocyte aging while knocking down PRDM16 impairs autophagic function and exacerbates aging in podocytes. In podocytes, overexpression of PRDM16 increases the expression of the key autophagy gene ATG4A, while knocking down PRDM16 reduces ATG4A expression levels. Conclusion: Upregulating PRDM16 can restore autophagic flux by increasing ATG4A expression, thereby delaying podocyte aging and improving glomerulosclerosis.