IFT88 deficiency in proximal tubular cells exaggerates cisplatin-induced injury by suppressing autophagy

Am J Physiol Renal Physiol. 2021 Jul 12. doi: 10.1152/ajprenal.00672.2020. Online ahead of print.ABSTRACTPrimary cilia are widely regarded as specialized sensors in differentiated cells that have been implicated in the regulation of cell proliferation, differentiation, and viability. We previously showed that shortening of primary cilia sensitizes cultured kidney tubular cells to cisplatin-induced apoptosis. IFT88 is an essential component for ciliogenesis and maintenance. Here, we have further examined the effect of proximal tubule-specific IFT88 ablation on cisplatin-induced acute kidney injury (AKI). In the study, more severe AKI occurred in IFT88 knockout mouse than age- and sex-matched wild type mice. Mechanistically, cisplatin stimulated autophagy in kidney tubular cells as an intrinsic protective mechanism. However, renal autophagy was severely impaired in IFT88 knockout mouse. In cultured HK-2 cells, cisplatin induced more apoptosis when IFT88 was knocked down. Tat-beclin 1 peptide, a specific autophagy activator, could partially prevent IFT88-associated cell death during cisplatin treatment, although cilium length was not improved significantly. Re-expression of IFT88 partially restored autophagy in IFT88-knockdown cells and suppressed apoptosis during cisplatin treatment. Taken together, these results indicate that defective autophagy in IFT88-deficient kidney cells and tissues contributes to the exaggerated AKI following cisplatin exposure.PMID:34251272 | DOI:10.11...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Source Type: research