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

Anne-Roos S Frenay,Harry Van Goor,Gerjan J Navis,Jacob Van Den Born,Femke Waanders,Miriam Boersema,Saleh Yazdani,Anne Marijn Van Der Graaf

doi:10.1371/journal.pone.0129732

Anne-Roos S Frenay, Harry Van Goor + Show 6 more

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https://doi.org/10.1371/journal.pone.0129732

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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.

Highlights

All progressive renal diseases, independent of their primary origin [1], lead to endstage renal fibrosis
The key finding of the current study is that following transient renal function decline induced by Angiotensin II (Ang II) infusion, all functional parameters–blood pressure, kidney function and doi:10.1371/journal.pone.0129732.g007
Glomerular desmin expression and thin interstitial collagen fibrils remained elevated in the kidney as shown by immunohistochemical and dotblot analysis

Summary

Introduction

All progressive renal diseases, independent of their primary origin [1], lead to endstage renal fibrosis. Under certain conditions during which the kidney suffers, for a limited period of time, from the consequences of hypertension and develops proteinuria there appears to be a remarkable renal capacity for self-repair. Recent data indicate that these patients are more vulnerable for the development of renal disease later in life [8,9,10,11]. This raises the question whether or not the repair mechanisms after short-term renal disease have been incomplete, thereby resulting in increased vulnerability to subsequent detrimental triggers

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