The cell cycle and acute kidney injury

Price, Peter M.; Safirstein, Robert; Megyesi, Judit

doi:10.1038/ki.2009.224

Cited by 183 publications

(182 citation statements)

References 114 publications

Supporting

Mentioning

160

Contrasting

Unclassified

Order By: Relevance

“…Remarkably, during AKI, the normally quiescent renal tubular cells reenter the cell cycle (29)(30)(31)(32)(33)(34), and blocking cell-cycle progression can reduce renal injury (28). Here, we provide evidence that the CDK4/6 pathway is activated early during AKI and demonstrate significant protective effects of CDK4/6 inhibitors in animal models of cisplatin-induced AKI.…”

mentioning

confidence: 56%

“…During AKI, along with cell death, cell-cycle activation is initiated in the normally quiescent renal tubular cells (29)(30)(31)(32)(33)(34). It is believed that this proliferative response may contribute to tissue regeneration (28,32,33,38), although this notion has been challenged recently (48). These issues notwithstanding, it is clear that a significant fraction of renal tubular cells enter the cell cycle during AKI (32,34) and that blocking or delaying cell-cycle entry has protective effects (28).…”

mentioning

confidence: 98%

“…These issues notwithstanding, it is clear that a significant fraction of renal tubular cells enter the cell cycle during AKI (32,34) and that blocking or delaying cell-cycle entry has protective effects (28). Studies with both genetic mouse models and pharmacological inhibitors have shown that inducing cell-cycle arrest by overexpression of p21 or treatment with CDK2 inhibitors prevents AKI, whereas knockdown of p21 increases renal tissue damage (28,29). Although CDK2-inhibiting strategies ameliorate AKI, CDK2-specific inhibitors that can be used clinically are unavailable.…”

mentioning

confidence: 99%

“…disease (26), nephritis (27), and acute kidney injury (AKI) (28). Remarkably, during AKI, the normally quiescent renal tubular cells reenter the cell cycle (29)(30)(31)(32)(33)(34), and blocking cell-cycle progression can reduce renal injury (28).…”

mentioning

confidence: 99%

“…It is believed that this proliferative response may contribute to tissue regeneration (28,32,33,38), although this notion has been challenged recently (48). These issues notwithstanding, it is clear that a significant fraction of renal tubular cells enter the cell cycle during AKI (32,34) and that blocking or delaying cell-cycle entry has protective effects (28). Studies with both genetic mouse models and pharmacological inhibitors have shown that inducing cell-cycle arrest by overexpression of p21 or treatment with CDK2 inhibitors prevents AKI, whereas knockdown of p21 increases renal tissue damage (28,29).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Pabla

Gibson

Buege

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

show abstract

mentioning

confidence: 56%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Pabla

Gibson

Buege

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

Hsp72 is an early and sensitive biomarker to detect acute kidney injury

et al. 2010

View full text Add to dashboard Cite

This study was designed to assess whether heat shock protein Hsp72 is an early and sensitive biomarker of acute kidney injury (AKI) as well as to monitor a renoprotective strategy. Seventy-two Wistar rats were divided into six groups: sham-operated and rats subjected to 10, 20, 30, 45 and 60 min of bilateral ischemia (I) and 24 h of reperfusion (R). Different times of reperfusion (3, 6, 9, 12, 18, 24, 48, 72, 96 and 120 h) were also evaluated in 30 other rats subjected to 30 min of ischemia. Hsp72 messenger RNA (mRNA) and protein levels were determined in both kidney and urine. Hsp72-specificity as a biomarker to assess the success of a renoprotective intervention was evaluated in rats treated with different doses of spironolactone before I/R. Renal Hsp72 mRNA and protein, as well as urinary Hsp72 levels, gradually increased relative to the extent of renal injury induced by different periods of ischemia quantified by histomorphometry as a benchmark of kidney damage. Urinary Hsp72 increased significantly after 3 h and continued rising until 18 h, followed by restoration after 120 h of reperfusion in accord with histopathological findings. Spironolactone renoprotection was associated with normalization of urinary Hsp72 levels. Accordingly, urinary Hsp72 was significantly increased in patients with clinical AKI before serum creatinine elevation. Our results show that urinary Hsp72 is a useful biomarker for early detection and stratification of AKI. In addition, urinary Hsp72 levels are sensitive enough to monitor therapeutic interventions and the degree of tubular recovery following an I/R insult.

show abstract

Protective effects of schizandrin and schizandrin B towards cisplatin nephrotoxicity in vitro

Bunel

Antoine

Nortier

et al. 2013

J of Applied Toxicology

View full text Add to dashboard Cite

Renal proximal tubular epithelial cells are the main targets of toxic drugs such as cisplatin (CisPt), an alkylating agent indicated for the treatment of solid organ tumors. Current techniques aiming at reducing nephrotoxicity in patients receiving CisPt are still not satisfactory as they can only partially prevent acute kidney injury. New nephroprotective strategies remain to be developed. In the present in vitro study, schizandrin (Schi) and schizandrin B (Schi B), major phytochemicals from Schisandra chinensis (Turcz.) Baill. fruits, were tested on HK-2 cells along four processes that could help alleviate CisPt toxicity. Results indicated that: (i) both Schi and Schi B enhanced cell survival via reducing apoptosis rate; (ii) only Schi showed moderate effects towards modulation of regeneration capacities of healthy cells; (iii) both Schi and Schi B limited extracellular matrix deposition; and (iv) both compounds could help preventing dedifferentiation processes via the β-catenin pathway. Schi and Schi B present promising activities for future development of protective agents against CisPt nephrotoxicity.

show abstract

The cell cycle and acute kidney injury

Cited by 183 publications

References 114 publications

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Hsp72 is an early and sensitive biomarker to detect acute kidney injury

Protective effects of schizandrin and schizandrin B towards cisplatin nephrotoxicity in vitro

Contact Info

Product

Resources

About