Research Progress in Stress-Induced Senescence of Renal Tubular Cells in Diabetic Nephropathy

YI Xianglin , HE Yani, CHEN Kehong

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Renal tubulointerstitial injury is an important pathophysiological basis that contributes to the progression of DN to end-stage renal disease. Stress-induced senescence of renal tubular epithelial cells (RTECs) forms a key link that causes tubulointerstitial injury. In recent years, it has been reported that organelles, such as endoplasmic reticulum, mitochondria, and lysosomes, in RTECs are damaged to varying degrees in DN, and that their functional imbalance may lead to stress-induced senescence of RTECs, thereby causing sustained cellular and tissue-organ damage, which in turn promotes the progression of the disease. However, the core mechanism underlying changes in the senescence microenvironment caused by stress-induced senescence of RTECs in DN is still not understood. In addition, the mechanism by which organelles lose homeostasis also needs to be further investigated. Herein, we described the specific pathophysiological mechanisms of renal tubular injury, stress-induced senescence of RTECs, and their association with organelles in the context of DN in order to provide reference for the next-step research, as well as the development of new therapeutic strategies.


Keywords: Renal tubular epithelial cells,  Stress-induced senescence,  Diabetic nephrology,  Review

 

Full Text:

PDF


References


SUN H， SAEEDI P， KARURANGA S， et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract，2022，183: 109119. doi: 10. 1016/j.diabres.2021.109119.

CHENG H T， XU X， LIM P S， et al. worldwide epidemiology of diabetes-related end-stage renal disease, 2000–2015. Diabetes Care，2021， 44(1): 89–97. doi: 10.2337/dc20-1913.

NYENGAARD J R， BENDTSEN T F. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec，1992，232(2): 194–201. doi: 10.1002/ar.1092320205.

SILVA F G. The aging kidney: a review-part Ⅱ. Int Urol Nephrol，2005， 37(2): 419–432. doi: 10.1007/s11255-004-0874-5.

DENIC A， GLASSOCK R J， RULE A D. Structural and functional changes with the aging kidney. Adv Chronic Kidney Dis，2016，23(1): 19–28. doi: 10.1053/j.ackd.2015.08.004.

YOON S G， GHEE J Y， YOO J A， et al. Role of NADPH oxidases in renal aging. Gerontology，2023，69(7): 852–865. doi: 10.1159/000529392.

VALLON V， THOMSON S C. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol，2020，16(6): 317–336. doi: 10.1038/s41581-020-0256-y.

DOSHI S M， FRIEDMAN A N. Diagnosis and management of type 2 diabetic kidney disease. Clin J Am Soc Nephrol，2017，12(8): 1366–1373. doi: 10.2215/CJN.11111016.

SLYNE J， SLATTERY C， MCMORROW T， et al. New developments concerning the proximal tubule in diabetic nephropathy: in vitro models and mechanisms. Nephrol Dial Transplant，2015，30(Suppl 4): iv60-7. doi: 10.1093/ndt/gfv264.

CHEVALIER R L. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction. Am J Physiol Renal Physiol，2016，311(1): F145–F161. doi: 10.1152/ajprenal. 00164.2016.

VALLON V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol，2011，300(5): R1009–R1022. doi: 10.1152/ajpregu.00809.2010.

GILBERT R E. Proximal tubulopathy: prime mover and key therapeutic target in diabetic kidney disease. Diabetes，2017，66(4): 791–800. doi: 10. 2337/db16-0796.

FU H， LIU S， BASTACKY S I， et al. Diabetic kidney diseases revisited: a new perspective for a new era. Mol Metab，2019，30: 250–263. doi: 10. 1016/j.molmet.2019.10.005.

WHITE K E， MARSHALL S M， BILOUS R W. Prevalence of atubular glomeruli in type 2 diabetic patients with nephropathy. Nephrol Dial Transplant，2008，23(11): 3539–3545. doi: 10.1093/ndt/gfn351.

HASEGAWA K， WAKINO S， SIMIC P， et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med，2013，19(11): 1496–1504. doi: 10. 1038/nm.3363.

NIHALANI D， SUSZTAK K. Sirt1-Claudin-1 crosstalk regulates renal function. Nat Med，2013，19(11): 1371–1372. doi: 10.1038/nm.3386. KIM S S， SONG S H， KIM I J， et al. Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy. Diabetes Care， 2013，36(3): 656–661. doi: 10.2337/dc12-0849.

SALMINEN A. Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases. Ageing Res Rev，2021，67: 101280. doi: 10.1016/j.arr.2021.101280.

STURMLECHNER I， DURIK M， SIEBEN C J， et al. Cellular senescence in renal ageing and disease. Nat Rev Nephrol，2017，13(2): 77–89. doi: 10. 1038/nrneph.2016.183.

SATO Y， YANAGITA M. Immunology of the ageing kidney. Nat Rev Nephrol，2019，15(10): 625–640. doi: 10.1038/s41581-019-0185-9.

SATRIANO J， MANSOURY H， DENG A， et al. Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol，2010，299(2): C374–C380. doi: 10.1152/ajpcell.00096. 2010.

LIU J， YANG J R， CHEN X M， et al. Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy. Am J Physiol Cell Physiol，2015， 308(8): C621–C630. doi: 10.1152/ajpcell.00096.2014.

LIU J， HUANG K， CAI G Y， et al. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell Signal，2014，26(1): 110–121. doi: 10.1016/j.cellsig.2013.10. 002.

CHEN J， CHEN K H， XIAO F， et al. Decoy receptor 2 mediation of the senescent phenotype of tubular cells by interacting with peroxiredoxin 1 presents a novel mechanism of renal fibrosis in diabetic nephropathy. Kidney Int，2020，98(3): 645–662. doi: 10.1016/j.kint.2020.03.026.

CHEN J， CHEN K H， WANG L M， et al. Decoy receptor 2 mediates the apoptosis-resistant phenotype of senescent renal tubular cells and accelerates renal fibrosis in diabetic nephropathy. Cell Death Dis，2022， 13(6): 522. doi: 10.1038/s41419-022-04972-w.

CHEN K， DAI H， YUAN J， et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis，2018，9(2): 105. doi: 10.1038/s41419-017-0127-z.

CHEN K， FENG L， HU W， et al. Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy. FASEB J，2019，33(3): 4571–4585. doi: 10.1096/fj.201801749RRR.

CHEN K， CHEN J， WANG L， et al. Parkin ubiquitinates GATA4 and attenuates the GATA4/GAS1 signaling and detrimental effects on diabetic nephropathy. FASEB J，2020，34(7): 8858–8875. doi: 10.1096/fj. 202000053R.

Al-DOUAHJI M， BRUGAROLAS J， BROWN P A， et al. The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy. Kidney Int，1999，56(5): 1691–1699. doi: 10.1046/j.1523-1755.1999.00728.x.

LIN Y， KURO-O M， SUN Z. Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice. Endocrinology，2013，154(10): 3855–3863. doi: 10.1210/en.2013-1053.

KUME S， KITADA M， KANASAKI K， et al. Anti-aging molecule, Sirt1: a novel therapeutic target for diabetic nephropathy. Arch Pharm Res， 2013，36(2): 230–236. doi: 10.1007/s12272-013-0019-4.

WANG Y， JIN M， CHENG C K， et al. Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives. Front Endocrinol (Lausanne)，2023，14: 1238927. doi: 10.3389/fendo. 2023.1238927.

TANG C， LIVINGSTON M J， LIU Z， et al. Autophagy in kidney homeostasis and disease. Nat Rev Nephrol，2020，16(9): 489–508. doi: 10.


Refbacks

  • There are currently no refbacks.