| dc.description.abstracteng | Alport syndrome is a hereditary nephritis that leads to ESRD in those affected between the ages of 20 and 30. The only long-term treatment option is a kidney transplantation. Since the waiting time for a kidney donation is currently in Germany around eight years, the affected family often wishes to do a living donation. Alport syndrome is caused by changes in the COL4A genes, which codes for components of collagen type IV α 3/4/5. In 85% of cases, Alport syndrome is inherited X-linked via the COL4A5 gene. Thus, the majority of Alport patients are male and children of heterozygous mothers. Although the mothers themselves may have damaged kidneys, they would like to help their child and donate a kidney. If the donation is carried out, the donor has to spend the rest of his life with the single kidney.
The situation described was simulated in a mouse model. COL4A3+/-, NPHS2+/R140Q and double heterozygous mice were used for the experiment. The control group consisted of wild type mice. The aim was to investigate the effect of a high-fat diet in heterozygous Alport mice with a single kidney. The R140Q polymorphism of the NPHS2 gene was also examined as a possible modifier gene. It encodes the protein podocin, which is part of the GBM. Modifier genes are suspected of having a significant influence on the course of Alport patients and thus being responsible for the strong variability in the course of the disease.
The mice were divided into three groups. One kidney was removed from the mice of the NEPH and Fett groups at around 138 days of age. The SHAM group received only one abdominal incision. After a one-week acclimatization phase, the mice in the fat group received nude mouse chow with a higher fat content. The control groups continued to receive the standard housing diet. Urine samples were regularly collected and weight determined throughout the experiment. Around the 180th day of life, the mice were sacrificed by craniocervical dislocation and blood samples, kidney(s) and liver were taken.
To assess the metabolic changes caused by the high-fat diet, body weight, cholesterol i. S. and the degree of fatty liver were examined. The body weight and degree of fatty liver in the fat group did not differ significantly from the control groups. The cholesterol concentration i. S. was about 30% higher than that of the SHAM group and about 23% higher than that of the NEPH group in the fat mice. Since neither type of food contained any cholesterol, more cholesterol must have been synthesized by the body through the diet. In humans, a maximum of 30% of the cholesterol level can be influenced by diet, so that a maximum effect may have been achieved. 5 Summary
The high-fat diet also had an effect on kidney function. Although the fat mice did not develop significant obesity, the COL4A3+/- -, the NPHS2+/R140Q - and the double heterozygous mice were scored significantly higher in the fibronectin score than in the NEPH group. According to this, diet-related increased interstitial fibrosis and glomerulosclerosis occurred. One possible explanation is the hormones secreted by adipose tissue. Thus, adipose tissue expresses RAAS components and adipokines. For example ANGII and the adipokine leptin have a pro-fibrotic effect in the kidney by increasing the expression of collagen types I, IV and fibronectin. If you are overweighted, the release of the adipokine adiponectin is suppressed. Adiponectin has a nephroprotective effect due to its anti-inflammatory and anti-oxidative properties. In addition, it appears to be important for the integrity of the glomerular slit membrane. Before external changes became visible, the high-fat diet may have increased the formation of visceral adipose tissue or changed the hormone secretion of the adipose tissue. Along with this, the urea concentration increased in the mice of the fat group. Significantly compared to the SHAM and NEPH groups. The SHAM and NEPH groups did not differ significantly from each other. The urea concentration i. S. is a renal function parameter. So the high-fat diet may have had a negative impact on kidney function. The urea concentration i. S. was slightly affected by the uninephrectomy, although there was no significant difference. Another cause would be the higher protein content in nude mouse feed, since urea is an end product of the amino acid metabolism and urea synthesis also increases with increased protein intake. The protein content of the nude mouse feed was 6% higher than that of the standard housing feed. There was no significant difference in proteinuria depending on the group or genotype. A significant difference in proteinuria could not be determined depending on the group or genotype. An increased accumulation of laminin-111 in the GBM, as is typical for Alport syndrome, could not be determined either.
It could be shown to some extent that a solitary kidney, especially with previous damage, can be negatively influenced by a high-fat diet, even before a visible obesity occurs. Simple measures such as a change in diet and physical activity may be able to effectively protect the solitary kidney after kidney donation in heterozygous Alport patients. 1% of the population is heterozygous for Alport syndrome. The prevalence of obesity is increasing worldwide. It is therefore essential to further investigate the influence of a high-fat diet and obesity on (single) kidneys with and without risk gene variants in order to provide those affected with recommendations and to initiate therapy at an early stage. | de |