Role of Aberrantly Activated Lysophosphatidic Acid Receptor 1 Signaling Mediated Inflammation in Renal Aging

• Published in: Cells (Basel, Switzerland) Switzerland), 2021-09, Vol.10 (10), p.2580
• Main Authors: Jin, Yongjie, Kim, Eun Nim, Lim, Ji Hee, Kim, Hyung Duk, Ban, Tae Hyun, Yang, Chul Woo, Park, Cheol Whee, Choi, Bum Soon
• Format: Article
• Language: English
• Subjects: Age; Aging; Animals; Antibodies; Biotechnology; Creatinine; Cytokines; DNA damage; Doxorubicin; Epithelial cells; Fibrosis; Humans; Hydrogen peroxide; Inflammation; Inflammation - genetics; kidney; Kidney diseases; Kidney Diseases - genetics; Kidneys; Lysophosphatidic acid; lysophosphatidic acid receptor 1; Male; Mice; NF-κB protein; nuclear factor-κB; Oxidative stress; Proteins; Receptors, Lysophosphatidic Acid - metabolism; Renal function; Senescence; Signal Transduction; Software; Urine
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10102580

The increasing load of senescent cells is a source of aging, and chronic inflammation plays a pivotal role in cellular senescence. In addition, senescent renal tubular epithelial cells are closely associated with renal aging. Lysophosphatidic acid (LPA) is a bioactive lipid mainly produced by the catalytic action of autotaxin (ATX), and its ligation to LPA receptor-1 (LPAR1) is associated with chronic inflammation and renal fibrosis; however, its role in renal aging is unclear. Male 2-, 12-, and 24-month-old C57BL/6 mice and Human renal proximal tubular epithelial cells (HRPTEpiC) were used in the present study. DNA damage and oxidative stress-induced senescence were simulated using doxorubicin (DOXO) and H O , respectively. The aged kidney showed decreased renal function, increased fractional mesangial area, and tubulointerstitial fibrosis. Both aged kidney and senescent cells showed increased levels of LPAR1, Nuclear factor κB (NF-κB), and inflammatory cytokines. In addition, knockdown reduced NF-κB and subsequent inflammatory cytokine induction, and -knockdown resulted in decreased LPAR1 expression. Our study revealed a positive feedback loop between LPAR1 and NF-κB, which reinforces the role of inflammatory response, suggesting that blocking of aberrantly activated LPAR1 may reduce excessive inflammation, thereby providing a new possible therapeutic strategy to attenuate renal aging.