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Incomplete Restoration of Angiotensin II-Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats.

Frenay AR, Yazdani S, Boersema M, van der Graaf AM, Waanders F, van den Born J, Navis GJ, van Goor H - PLoS ONE (2015)

Bottom Line: Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values.However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated.These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands.

ABSTRACT
Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p<0.001) and proteinuria (51.4 ± 6.3 vs. 14.7 ± 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 ± 0.5 vs. 4.9 ± 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 ± 4.8 vs. 3.6 ± 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 ± 0.4 vs. 2.2 ± 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.

No MeSH data available.


Related in: MedlinePlus

Effects of Ang II infusion and withdrawal on tubular damage.Havcr1 mRNA (A) and protein (B) levels were increased by Ang II infusion. After stopping Ang II infusion, recovery of proximal tubular damage was established, evidenced by control levels of Havcr1 mRNA and Kim-1 protein levels in Ang II infused rats. Representative photomicrographs of Kim-1 stained renal sections (C). (### p<0.001 vs. control at time of biopsy; ***p<0.001 vs. Ang II at time of biopsy).
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pone.0129732.g002: Effects of Ang II infusion and withdrawal on tubular damage.Havcr1 mRNA (A) and protein (B) levels were increased by Ang II infusion. After stopping Ang II infusion, recovery of proximal tubular damage was established, evidenced by control levels of Havcr1 mRNA and Kim-1 protein levels in Ang II infused rats. Representative photomicrographs of Kim-1 stained renal sections (C). (### p<0.001 vs. control at time of biopsy; ***p<0.001 vs. Ang II at time of biopsy).

Mentions: Ang II infusion induced tubular dilatation and atrophy as reflected by a significant increase in Havcr1 mRNA and KIM-1 protein expression (p<0.001) (Fig 2A and 2B) and Spp1 mRNA and OPN protein expression (p<0.001 and p<0.001) (Fig 3A and 3B) when compared to control rats. A complete reversibility of tubular damage was seen eight weeks after cessation of Ang II, evidenced by a reduction to control levels of both Havcr1 mRNA and KIM-1 protein expression (p<0.001) as well as SPP1 mRNA expression (p<0.001). Control rats showed a slight increase in SPP1 mRNA (p<0.01) and OPN protein (p<0.05) expression over the course of the study. At time of sacrifice, there was no difference in OPN protein expression between Ang II-infused rats and control rats. Glomerular desmin protein expression was increased 7.4-fold after three weeks of Ang II infusion (p<0.01) (Fig 4A). There was no recovery of desmin expression after cessation of Ang II infusion, and desmin protein expression of rats previously subjected to Ang II infusion even increased over the weeks when compared to their biopsy levels (p<0.05). Glomerular desmin expression of NaCl-infused rats also progressed over the weeks (p<0.001). At time of termination, Ang II-infused rats still had significantly higher levels of desmin protein expression when compared to control rats (p<0.05). Three weeks of Ang II infusion did not result in focal segmental glomerular sclerosis (Fig 5).


Incomplete Restoration of Angiotensin II-Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats.

Frenay AR, Yazdani S, Boersema M, van der Graaf AM, Waanders F, van den Born J, Navis GJ, van Goor H - PLoS ONE (2015)

Effects of Ang II infusion and withdrawal on tubular damage.Havcr1 mRNA (A) and protein (B) levels were increased by Ang II infusion. After stopping Ang II infusion, recovery of proximal tubular damage was established, evidenced by control levels of Havcr1 mRNA and Kim-1 protein levels in Ang II infused rats. Representative photomicrographs of Kim-1 stained renal sections (C). (### p<0.001 vs. control at time of biopsy; ***p<0.001 vs. Ang II at time of biopsy).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4464893&req=5

pone.0129732.g002: Effects of Ang II infusion and withdrawal on tubular damage.Havcr1 mRNA (A) and protein (B) levels were increased by Ang II infusion. After stopping Ang II infusion, recovery of proximal tubular damage was established, evidenced by control levels of Havcr1 mRNA and Kim-1 protein levels in Ang II infused rats. Representative photomicrographs of Kim-1 stained renal sections (C). (### p<0.001 vs. control at time of biopsy; ***p<0.001 vs. Ang II at time of biopsy).
Mentions: Ang II infusion induced tubular dilatation and atrophy as reflected by a significant increase in Havcr1 mRNA and KIM-1 protein expression (p<0.001) (Fig 2A and 2B) and Spp1 mRNA and OPN protein expression (p<0.001 and p<0.001) (Fig 3A and 3B) when compared to control rats. A complete reversibility of tubular damage was seen eight weeks after cessation of Ang II, evidenced by a reduction to control levels of both Havcr1 mRNA and KIM-1 protein expression (p<0.001) as well as SPP1 mRNA expression (p<0.001). Control rats showed a slight increase in SPP1 mRNA (p<0.01) and OPN protein (p<0.05) expression over the course of the study. At time of sacrifice, there was no difference in OPN protein expression between Ang II-infused rats and control rats. Glomerular desmin protein expression was increased 7.4-fold after three weeks of Ang II infusion (p<0.01) (Fig 4A). There was no recovery of desmin expression after cessation of Ang II infusion, and desmin protein expression of rats previously subjected to Ang II infusion even increased over the weeks when compared to their biopsy levels (p<0.05). Glomerular desmin expression of NaCl-infused rats also progressed over the weeks (p<0.001). At time of termination, Ang II-infused rats still had significantly higher levels of desmin protein expression when compared to control rats (p<0.05). Three weeks of Ang II infusion did not result in focal segmental glomerular sclerosis (Fig 5).

Bottom Line: Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values.However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated.These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands.

ABSTRACT
Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 ± 10.43 vs. 146 ± 1.4 mmHg, p<0.001) and proteinuria (51.4 ± 6.3 vs. 14.7 ± 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 ± 0.5 vs. 4.9 ± 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 ± 4.8 vs. 3.6 ± 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 ± 0.4 vs. 2.2 ± 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage.

No MeSH data available.


Related in: MedlinePlus