Pathophysiology of Unilateral Ureteral Obstruction: Studies From Charlottesville to New York

Vaughan, E. Darracott; Marion, D.; Poppas, Dix P.; Felsen, Diane

doi:10.1097/01.ju.0000144286.53562.95

Cited by 99 publications

(85 citation statements)

References 15 publications

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“…For these reasons, we tested whether TGFb1 stimulation increased DPPIV activity because TGFb1 is a well-known central player in renal fibrosis in the UUO model. 32,33 Interestingly, we found that exogenous administration of TGFb1 markedly enhanced DPPIV activity in proximal tubule cells. These results are in contrast with those from a previous study using human peritoneal mesothelial cells and human dermal fibroblasts, which shows that exogenous TGFb1 decreases DPPIV activity.…”

Section: Discussionmentioning

confidence: 84%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

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Section: Discussionmentioning

confidence: 84%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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“…55 The UUO maneuver mimics, in an accelerated manner, the different stages of obstructive nephropathy leading to tubulointerstitial fibrosis: cellular infiltration, tubular proliferation and apoptosis, EMT, myofibroblast accumulation, increased ECM deposition, and tubular atrophy. [55][56][57][58] In this study, we examined the role of TRPC3 in renal fibroblasts and evaluated the therapeutic efficiency of TRPC3 inhibition in obstructive nephropathy in rat and TRPC3 knockout (TRPC3 2/2 ) mouse UUO models.…”

mentioning

confidence: 99%

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Saliba¹,

Karam²,

Smayra

et al. 2015

Journal of the American Society of Nephrology

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Transient receptor potential canonical (TRPC) Ca 2+ -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II-and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca 2+ entry in these cells, which was detected by fura-2 Ca 2+ imaging. TRPC3 blockade or Ca 2+ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signalregulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca 2+ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca 2+ -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.

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“…As expected, in patients with unilateral ureteral obstruction and normal contralateral kidney, compensation mechanism can overcome, though partially, and reabsorb water and electrolytes (12,16). The vasopressin is an antidiuretic agent that acts on the receptors of basolateral membrane of kidney collecting duct cells, which causes the fusion of vesicles containing aquapurins into apical cells of the collecting ducts.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Citrate Can Reduce Pathological Post-obstructive Diuresis in a Rat Model ofBilateral Ureteral Obstruction

Mombeini¹,

Dadfar²,

Khazaeli³

et al. 2017

Jentashapir J Helath Res

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Purpose: The current study aimed at assessing the effect of oral sildenafil citrate on postobstructive diuresis and urinary electrolyte changes after the management of bilateral ureteral obstruction (BUO). Methods: Twenty-eight adult Munich-Wistar male rats were subjected to the surgery-induced BUO for 24 hours. In intervention group (n = 14) sildenafil citrate 200 mg/kg food was administered from the operation day for 72 hours, while in control group (n = 14) no drug was used. Daily urinary volume, urine sodium (mEq/day), potassium (mEq/day), and osmolality (mOsm/kg H2O) were measured on the day before BUO and for 2 days after BUO release. Results: In comparison to the control group, postobstructive diuresis was significantly lower in the sildenafil group (P value < 0.001), while urinary sodium and osmolality were both preserved better in this group (P value < 0.001); however, there were no significant difference in potassium level between the groups (P value = 0.285). Conclusions: Oral sildenafil citrate significantly decreased postobstructive diuresis and preserved urine sodium and osmolality near normal. These 2 effects mean a better preservation of renal function, while preventing massive postobstructive diuresis.

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Pathophysiology of Unilateral Ureteral Obstruction: Studies From Charlottesville to New York

Cited by 99 publications

References 15 publications

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Sildenafil Citrate Can Reduce Pathological Post-obstructive Diuresis in a Rat Model ofBilateral Ureteral Obstruction

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