Urinary collagen degradation products as early markers of progressive renal fibrosis

Hijmans, Ryanne S.; Rasmussen, Daniel Guldager Kring; Yazdani, Saleh; Navis, Gerjan; Goor, Harry van; Karsdal, Morten A.; Genovese, Federica; Born, Jacob van den

doi:10.1186/s12967-017-1163-2

Cited by 35 publications

(23 citation statements)

References 47 publications

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“…Numerous recent studies have confirmed the association of urinary C3M (uC3M) with renal fibrosis in different rat models including 5/6 Nx, anti-Thy 1.1, adenine nephropathy and type 2 diabetic nephropathy models (Papasotiriou et al 2015;Dower et al 2017). In a proteinuria-driven rat model, uC3M levels were elevated and measurable even before being histologically detectable (Hijmans et al 2017). In type 1 diabetes these markers have not been tested yet and the effect of RAASi treatment on their excretion has not been investigated either.…”

Section: Introductionmentioning

confidence: 89%

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RAAS inhibitors directly reduce diabetes‐induced renal fibrosis via growth factor inhibition

Kőszegi

Molnár

Lionetti

et al. 2018

The Journal of Physiology

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Key points Increased activation of the renin‐angiotensin‐aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to diabetic kidney disease.The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect.We found that RAASi ameliorate diabetes‐induced renal interstitial fibrosis and decrease profibrotic growth factor production.RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia‐induced growth factor production and thereby fibroblast activation.These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis. AbstractIn diabetic kidney disease (DKD) increased activation of renin‐angiotensin‐aldosterone system (RAAS) contributes to renal fibrosis. Although RAAS inhibitors (RAASi) are the gold standard therapy in DKD, the mechanism of their antifibrotic effect is not yet clarified. Here we tested the antifibrotic and renoprotective action of RAASi in a rat model of streptozotocin‐induced DKD. In vitro studies on proximal tubular cells and renal fibroblasts were also performed to further clarify the signal transduction pathways that are directly altered by hyperglycaemia. After 5 weeks of diabetes, male Wistar rats were treated for two more weeks per os with the RAASi ramipril, losartan, spironolactone or eplerenone. Proximal tubular cells were cultured in normal or high glucose (HG) medium and treated with RAASi. Platelet‐derived growth factor (PDGF) or connective tissue growth factor (CTGF/CCN2)‐induced renal fibroblasts were also treated with various RAASi. In diabetic rats, reduced renal function and interstitial fibrosis were ameliorated and elevated renal profibrotic factors (TGFβ1, PDGF, CTGF/CCN2, MMP2, TIMP1) and alpha‐smooth muscle actin (αSMA) levels were decreased by RAASi. HG increased growth factor production of HK‐2 cells, which in turn induced activation and αSMA production of fibroblasts. RAASi decreased tubular PDGF and CTGF expression and reduced production of extracellular matrix (ECM) components in fibroblasts. In proximal tubular cells, hyperglycaemia‐induced growth factor production increased renal fibroblast transformation, contributing to the development of fibrosis. RAASi, even in non‐antihypertensive doses, decreased the production of profibrotic factors and directly prevented fibroblast activation. All these findings suggest a novel therapeutic role for RAASi in the treatment of renal fibrosis.

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Section: Introductionmentioning

confidence: 89%

“…In a proteinuria‐driven rat model, uC3M levels were elevated and measurable even before being histologically detectable (Hijmans et al . ). In type 1 diabetes these markers have not been tested yet and the effect of RAASi treatment on their excretion has not been investigated either.…”

Section: Introductionmentioning

confidence: 97%

RAAS inhibitors directly reduce diabetes‐induced renal fibrosis via growth factor inhibition

Kőszegi

Molnár

Lionetti

et al. 2018

The Journal of Physiology

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“…167 Elevated urinary levels of PIIINP were associated with CKDprogression in elderly patients. 168 MMP-mediated collagen I and III degradation fragments, C1M and C3M, were shown to be a potential biomarker in animal models of fibrosis 169,170 and acute kidney injury. 171 In two cohorts of IgA-nephropathy patients, collagen III-turnover suggested a profibrotic ECM remodeling with increasing CKD stage, with steadily increasing Pro-C3 as a marker of collagen III production and progressively decreasing C3M as a marker of collagen III degradation.…”

Section: Renal Ecm Components-biomarker Potential?mentioning

confidence: 99%

Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold

Bülow

Boor

2019

J Histochem Cytochem.

277

187

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Kidney fibrosis is the common histological end-point of progressive, chronic kidney diseases (CKDs) regardless of the underlying etiology. The hallmark of renal fibrosis, similar to all other organs, is pathological deposition of extracellular matrix (ECM). Renal ECM is a complex network of collagens, elastin, and several glycoproteins and proteoglycans forming basal membranes and interstitial space. Several ECM functions beyond providing a scaffold and organ stability are being increasingly recognized, for example, in inflammation. ECM composition is determined by the function of each of the histological compartments of the kidney, that is, glomeruli, tubulo-interstitium, and vessels. Renal ECM is a dynamic structure undergoing remodeling, particularly during fibrosis. From a clinical perspective, ECM proteins are directly involved in several rare renal diseases and indirectly in CKD progression during renal fibrosis. ECM proteins could serve as specific non-invasive biomarkers of fibrosis and scaffolds in regenerative medicine. The gold standard and currently only specific means to measure renal fibrosis is renal biopsy, but new diagnostic approaches are appearing. Here, we discuss the localization, function, and remodeling of major renal ECM components in healthy and diseased, fibrotic kidneys and the potential use of ECM in diagnostics of renal fibrosis and in tissue engineering.

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“…All these kidney injury markers were highly expressed in the adenine-induced group of rats, whereas these levels were near normal in the rapamycin-treated group. Furthermore, the development of injury would lead to profibrotic and fibrotic events, which are indicated by the increase in uC1M and uC3M, the late renal fibrotic markers [33] that are observed in the urine of the CKD animals.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of mTOR Signaling Is the Major Response Element in the Rescue Pathway of Chronic Kidney Disease in Rats

Wang¹,

Chai²,

Lu³

et al. 2020

Neuroimmunomodulation

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Background: Modern lifestyle changes and the interlinking of non-communicable diseases result in the development of chronic kidney disease (CKD). While research has focused on attenuating the CKD, the role of mTOR in the progression of CKD is still unclear. Objectives: The current investigation was undertaken to study the role of mTOR-mediated signaling in CKD using Wistar male rats and adenine-induced CKD as an experimental model. Method: The animals were divided into 3 groups, representing control, CKD, and rapamycin-pretreated rats. At the end of the experimental period, blood biochemical indexes on kidney function and expression levels of fibrotic markers, including TGF-β, PAI-1, α-smooth muscle action, fibronectin, CTGF, and collagen-1, were analyzed. In addition, kidney injury markers such as kim-1, cystatin-C, NAG, and NGAL, indicating a progressive fibrotic response, were also studied. Results: The results suggest that mTOR inhibition significantly attenuated the induction of fibrosis, with restored serum creatinine and blood urea nitrogen levels. Intriguingly, the microRNA (miRNA) analysis revealed an increased expression of miR-193-5p, miR-221, miR-212, and miR-183-5p in CKD, while an increased mRNA expression of anti-inflammatory cytokines and reduced level of pS6K with attenuated miRNA was found in rapamycintreated rats compared to the CKD animals. Conclusion: Activation of mTOR is the major responsive element with activation of miRNAs as an elementary role in the progression of kidney disease. Hence, targeting mTOR would be a possible strategy of treatment for CKD.

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Urinary collagen degradation products as early markers of progressive renal fibrosis

Cited by 35 publications

References 47 publications

RAAS inhibitors directly reduce diabetes‐induced renal fibrosis via growth factor inhibition

RAAS inhibitors directly reduce diabetes‐induced renal fibrosis via growth factor inhibition

Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold

Attenuation of mTOR Signaling Is the Major Response Element in the Rescue Pathway of Chronic Kidney Disease in Rats

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