Research ArticleNorUrsodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice
Graphical abstract
Introduction
Impairment of renal function in liver disease represents a severe life-threatening event and may be related to numerous causes including hepatorenal syndrome (HRS) [1], [2], [3], [4]. Patients with cirrhosis with concomitant infections and those with severe jaundice represent a high-risk group with dismal prognosis [5], [6], [7], [8]. Notably, infection and cholestasis commonly co-exist as inflammation-induced cholestasis [9], and infection also represents a major trigger for acute on chronic liver failure (ACLF) [10].
Specific kidney alterations due to cholestasis are known as cholemic nephropathy, also referred to as bile cast nephropathy [11], [12], [13]. These umbrella terms cover impaired renal function in patients with jaundice with tubular epithelial damage predominantly at the level of distal nephron segments together with characteristic intratubular bile cast formation [13], [14], [15].
Aiming to explore novel treatment strategies, we had recently modeled cholemic nephropathy in long-term common bile duct ligated (CBDL) mice [16]. We showed that compensatory renal instead of biliary excretion of bile acids leads to: (i) tubular epithelial injury, cast formation, basement membrane defects; (ii) leakage of urine into the kidney parenchyma; (iii) induction of a reactive phenotype of tubular epithelial cells resulting in interstitial nephritis, and finally (iv) kidney fibrosis.
Modified bile acid derivatives open exciting novel therapeutic opportunities for liver disorders and beyond [17], [18]. Norursodeoxycholic acid (norUDCA) is a side-chain shortened derivative of UDCA [19], [20] and was recently tested in a phase II clinical trial in patients with primary sclerosing cholangitis. In mouse models of cholestasis, NorUDCA increases bile acid-independent, bicarbonate-dependent bile flow and induces alternative secretory routes for potentially toxic endogenous bile acids by ameliorating their metabolism and basolateral hepatocellular export [20], [21], [22]. Importantly, norUDCA also protects the kidney by preventing collecting duct injury after 3 days of CBDL in mice [16]. Consequently, norUDCA may represent an attractive substance for the treatment of cholemic nephropathy, especially in advanced cholestatic liver disease. Since currently there is no medical treatment available for cholemic nephropathy, we performed a longitudinal study in a well-characterized mouse model in order to unravel the therapeutic potential of norUDCA and its mechanism(s) of action.
Section snippets
Animal experiments, serum biochemical analysis and histology
All experimental protocols were approved by the local authorities (BMWF-66.010/0045-II/10b/2010, BMWF-66.010/0012-II/3b/2014 and BMWFW-66.010/0129-WF/V/3b/2016) according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the U.S. National Academy of Science (National Institutes of Health publication 86–23, revised 1985). Experiments were performed with 8–10 week-old male C57BL/6 mice (25 to 30 g body weight), housed with a 12:12 h light:dark cycle and
NorUDCA protects long-term CBDL mice from cholemic nephropathy
Both experimental arms that were used to study the therapeutic efficacy of norUDCA in cholemic nephropathy (norUDCA for prevention and norUDCA for rescue, Fig. 1A) led to significant amelioration of the renal phenotype. As such, long-term CBDL in chow-fed CBDL mice resulted in macroscopically greenish kidneys with an irregular surface (Fig. 1B, left pair of kidneys), while kidneys of norUDCA-fed CBDL mice (norUDCA for prevention, Fig. 1B, right pair of kidneys) appeared normal. Upon urine
Discussion
Here we show that norUDCA effectively and specifically ameliorates cholemic nephropathy in long-term CBDL mice, both in morphology and function. Importantly, the kidney protective effects of norUDCA are unlikely to be consequences of improved liver disease. Rather, in such long-term obstructive cholestasis norUDCA feeding did not positively affect liver function and histology as compared to chow-fed mice. Thus, our findings suggest that at least in our experimental set up there is a
Financial support
This work was supported by a grant (P25911-B19) from the Austrian Science Foundation (to P.F.), the regional agreement on medical training and clinical research (ALF) between Region Västra Götaland and Sahlgrenska University Hospital (to H.U.M.) and an unrestricted research grant from Dr. Falk Pharma GmbH. TBH was supported by the DFG, ERC and BMBF.
Conflict of interest
The Medical University of Graz has filed norUDCA patents for the treatment of liver diseases and arteriosclerosis, and P.F. and M.T. are co-inventors (WO2006119803 and WO20099013334); E.K. received an unrestricted research grant and norUDCA from Dr. Falk Pharma GmbH, Freiburg, Germany; P.F. and M.T. received an unrestricted research grant, norUDCA, travel grants, and advisory board fees from Dr. Falk Pharma GmbH; A.W. and H.U.M. received travel grants from Dr. Falk Pharma GmbH.
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Authors’ contributions
EK is responsible for experimental set up, measurements, analysis of data, interpretation of data and manuscript writing; KE, MJP, AHK, MT, HUM and ARR helped with study design, interpretation of data and drafting of the manuscript; BF performed LPS experiments together with KE; HUM, MS and AW performed UPLC-MS/MS analyses of bile acids; SR performed experiments together with EK; FG and TBH supported the I/R and UUO experiments on a collaborative base and helped interpreting data and drafting
Acknowledgment
This paper is dedicated to Prof. Alan Hofmann as an outstanding scientific mentor, indispensable interlocutor, and leading scientist in “bileology”. We thank Dr. Wolfgang Erwa (Graz) and colleagues for performing liver tests and Judith Gumhold, Dagmar Silbert, Andrea Deutschmann, Dietmar Glänzer, and Katharina Kinslechner for excellent technical assistance. We would also like to give our sincere thanks to the participants of the 14th Pichlschloss Transport Meeting (July 2013) organized by Prof.
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