Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background

Puri, Tipu S.; Shakaib, Mohammed; Chang, Anthony; Mathew, Liby; Olayinka, Oladunni; Minto, Andrew W.; Sarav, Menaka; Hack, Bradley K.; Quigg, Richard J.

doi:10.1152/ajprenal.00384.2009

Cited by 71 publications

(88 citation statements)

References 33 publications

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“…See Supplemental Methods for details. For renal function analysis, reversible UUO was performed (22). Briefly, 12-weekold mice were anesthetized and the right ureter was then ligated.…”

Section: Methodsmentioning

confidence: 99%

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Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Fujiu

Manabe²,

Nagai³

2011

J. Clin. Invest.

220

209

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Renal tubulointerstitial damage is the final common pathway leading from chronic kidney disease to endstage renal disease. Inflammation is clearly involved in tubulointerstitial injury, but it remains unclear how the inflammatory processes are initiated and regulated. Here, we have shown that in the mouse kidney, the transcription factor Krüppel-like factor-5 (KLF5) is mainly expressed in collecting duct epithelial cells and that Klf5 haploinsufficient mice (Klf5 +/-mice) exhibit ameliorated renal injury in the unilateral ureteral obstruction (UUO) model of tubulointerstitial disease. Additionally, Klf5 haploinsufficiency reduced accumulation of CD11b + F4/80 lo cells, which expressed proinflammatory cytokines and induced apoptosis among renal epithelial cells, phenotypes indicative of M1-type macrophages. By contrast, it increased accumulation of CD11b + F4/80 hi macrophages, which expressed CD206 and CD301 and contributed to fibrosis, in part via TGF-β production -phenotypes indicative of M2-type macrophages. Interestingly, KLF5, in concert with C/EBPα, was found to induce expression of the chemotactic proteins S100A8 and S100A9, which recruited inflammatory monocytes to the kidneys and promoted their activation into M1-type macrophages. Finally, assessing the effects of bone marrow-specific Klf5 haploinsufficiency or collecting duct-or myeloid cell-specific Klf5 deletion confirmed that collecting duct expression of Klf5 is essential for inflammatory responses to UUO. Taken together, our results demonstrate that the renal collecting duct plays a pivotal role in the initiation and progression of tubulointerstitial inflammation.

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“…See Supplemental Methods for details. For renal function analysis, reversible UUO was performed (22). Briefly, 12-weekold mice were anesthetized and the right ureter was then ligated.…”

Section: Methodsmentioning

confidence: 99%

“…To analyze the effects of Klf5 haploinsufficiency on renal dysfunction, we employed a reversible UUO procedure (22). Initially, the right ureter was obstructed for 3 days, and then the obstruction was released.…”

Section: Klf5 Haploinsufficiency Ameliorates Renal Injury and Dysfuncmentioning

confidence: 99%

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Fujiu

Manabe²,

Nagai³

2011

J. Clin. Invest.

220

209

View full text Add to dashboard Cite

show abstract

“…UUO and release were performed similar to previously described techniques (6,43). Transgene expression was induced in 2-mo-old female mice using either 5-mg 21-day release or 12.5-mg 60-day release subcutaneous testosterone pellets (Innovative Research of America, Sarasota, FL) for 2 wk.…”

Section: Methodsmentioning

confidence: 99%

Increased expression of p21^WAF1/CIP1 in kidney proximal tubules mediates fibrosis

Megyesi

Tarcsafalvi

et al. 2015

American Journal of Physiology-Renal Physiology

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Tissue fibrosis is a major cause of death in developed countries. It commonly occurs after either acute or chronic injury and affects diverse organs, including the heart, liver, lung, and kidney. Using the renal ablation model of chronic kidney disease, we previously found that the development of progressive renal fibrosis was dependent on p21WAF1/Cip1 expression; the genetic knockout of the p21 gene greatly alleviated this disease. In the present study, we expanded on this observation and report that fibrosis induced by two different acute injuries to the kidney is also dependent on p21. In addition, when p21 expression was restricted only to the proximal tubule, fibrosis after injury was induced in the whole organ. One molecular fibrogenic switch we describe is transforming growth factor-β induction, which occurred in vivo and in cultured kidney cells exposed to adenovirus expressing p21. Our data suggests that fibrosis is p21 dependent and that preventing p21 induction after stress could be a novel therapeutic target.

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“…It has however been reported that restoration of the ureter can be cumbersome due to adhesions of the tissue around the ligature; the inner walls of the ureter can stay attached to each other thereby preventing the necessary recovery of the urinary flow. This can be improved by clamping the ureter and subsequently replacing the clip every 2 days to prevent the inner walls of the ureter from merging, 47 or by using an alternative strategy in which the obstructed ureter is replaced by the contralateral (healthy) kidney. Currently, both methods to reverse the ureter obstruction are still in the developmental stage and further validation is needed to obtain a reproducible model, representative of tubulointerstitial fibrosis in human.…”

Section: Inhibitory Effects On Downstream Profibrotic Factorsmentioning

confidence: 99%

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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Background: Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis. Methods: A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice. Results: The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects. Conclusion: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.

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Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background

Cited by 71 publications

References 33 publications

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Increased expression of p21^WAF1/CIP1 in kidney proximal tubules mediates fibrosis

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

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Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background

Cited by 71 publications

References 33 publications

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

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Increased expression of p21^WAF1/CIP1 in kidney proximal tubules mediates fibrosis