Identifying the role of receptors
Chronic kidney disease (CKD) affects more than 10% of the population and is associated with significantly increased morbidity, including cardiovascular disease and early death. Proteinuria is an essential marker of CKD and associated with a higher risk of complications and progression to end stage renal disease requiring dialysis. Proteinuria may reflect renal dysfunction at several levels including endothelial dysfunction, glomerular damage and tubular dysfunction.
Key molecules including the two major renal proximal tubule endocytic receptors, megalin and cubilin, involved in tubular protein reabsorption, have been demonstrated to be of importance for normal renal physiology and uptake of filtered hormones, vitamins, toxins and drugs.
Current studies are aimed at identifying the role of these receptors and associated cellular processes for the development and progression of both acute and chronic kidney injury. These studies explore disease mechanisms in acute kidney injury (AKI) and CKD, and identify potential new targets for intervention in these conditions associated with great morbidity and huge economic costs.
The studies include the exploration of:
- Megalin and cubilin as mediators of AKI involving the uptake of toxins and drugs.
- Megalin and cubilin as modulators of the proximal tubule cellular response to toxic and ischemic renal injury.
- The role of megalin and cubilin for the progression of CKD as regulators of protein-induced renal tubular cell and interstitial injury including tubular complement activation.
- The role of megalin and cubilin in proximal tubule metabolic dysfunction in CKD.
- The potential role of these receptors in the regulation of blood pressure and maintnenance of fluid and electrolyte balance.
These mechanisms are investigated in both animal studies and observational studies in humans. Experimental models of AKI and CKD are tested in relevant mouse models of receptor knockouts, and we are developing assays for the evaluation of proximal tubule endocytic function in humans. These are correlated with disease progression and complications to identify potential and clinically relevant consequences of receptor dysfunction in CKD.
These studies which are fundamental for potential new treatments of AKI and CKD are performed in close collaboration between the Department of Renal Medicine, the Department of Biomedicine, Aarhus University and the Department of Cardiovascular and Renal Research, University of Southern Denmark.
Gene-phenotype variation in ADPKD
Autosomal dominant polycystic kidney disease (ADPKD) is the underlying cause in about 10% of all patients with end stage renal disease. It is characterized by the formation and growth of renal cysts obstructing normal tubules and causing inflammation, interstitial fibrosis and eventually end stage renal disease.
Most cases are caused by variants in either the PKD1 or the PKD2 gene. Both the involved genes and the type of variant have been shown to provide significant prognostic information in relation to the risk of early progression to end stage renal disease. Screening for pathogenic variants of both PKD1 and PKD2 has been estimated to identify a likely pathogenic variant in 90% of families with ADPKD. In the remaining 10% of the families pathogenic variants may be located to non-exon regions of PKD1 or PKD2 or the variants may be in genes, which have not previously been associated with ADPKD. Knowing the genotype in the individual families will be instrumental for an efficient treatment, as the genotype provides information on the prognosis. In addition to the genotype, biomarkers (biological molecules) are expected to provide prognostic information to identify patients with rapid progression that may benefit from treatment, initiated in early stages of the disease.
Pharmacological modulation of cellular pathways downstream of the polycystins has been shown to inhibit cyst growth and preserve renal function in various mouse models of cystic kidney disease; however, most of these interventions have shown limited effect in humans. Several factors may explain the lack of efficacy in humans including insufficient drug concentration within the renal tissue, in part due to the risk of toxicity and side effects. Targeting drugs to the renal cysts may provide a way to increase drug concentrations and, thus, efficacy in humans without intolerable side effects. In ADPKD, cysts originate, at least in part, from proximal tubules, suggesting that the megalin and cubilin receptors could be utilized for drug targeting. Preliminary results from our laboratory using immunhistochemistry on both mouse and human tissues have shown that megalin and cubilin are expressed in epithelial cells of some cysts, indicating the feasibility of this concept. In addition, the extra-renal expression of these receptors appears to be limited, suggesting that the use of these as drug carrying receptors may be associated with fewer side effects.
Current studies aim to establish new methods to improve diagnostics and personalize treatment in ADPKD by combining clinical genetics, clinical nephrology and basal research. We will identify new new causative and disease modifying genes variants associated with ADPKD and relate these to biomarkers that reliably can predict the prognosis in ADPKD. Furthermore, we will examine the expression and function of the protein and potential drug receptors megalin and cubilin in cyst tissue. The project should form basis for a more personalized treatment targeted those patients in greatest risk of progression and with greater efficacy and fewer side effects. The studies are performed in close collaboration between the Department of Renal Medicine, the Department of Biomedicine and the Department of Clinical Genetics, Aarhus University and Aarhus University Hospital.
- Institute of Biomedicine, Aarhus University
att. Associate professor, Rikke Nielsen and
assistant professor, Kathrin Weyer
- University of Southern Denmark
att. Head of Research Unit, Professor Boye L. Nielsen
- Department of Clinical Genetics, Aarhus University Hospital
- Department of Clinical Genetics, Vejle Hospital
- Renal Functional Magnetic Resonance Imaging in Healthy Persons - Reproducibility and Impact of Stress
- Urinary complement activation in IgA nephropathy
- Urinary proteases and sodium retention in nephrotic syndrome in mice
- Megalin and blood pressure regulation in mice - role of megalin and cubilin
- Urinary complement activation in nephrotic syndrome in mice
- Gene-photype variations in ADPKD