About 12.5 million people worldwide have autosomal dominant polycystic kidney disease (PKD), a condition caused by mutations in one of two genes, PKD1 or PKD2. It is the fourth leading cause of kidney failure in the United States, with around 600,000 cases. These mutations cause dilation of the kidney tubules, the tubes that filter blood and generate urine, forming cysts that grossly enlarge the kidneys. In about 50% of patients, these cysts eventually cause kidney failure, requiring dialysis or a transplant. Although there is only one drug approved for treatment, it simply slows the decline in kidney function. Further treatments for this condition are urgently needed, but the molecular mechanisms that cause PKD to develop and progress are not yet fully known. Now, UT Southwestern researchers report that a chemical modification of diet-influenced RNA appears to play a key role in the disease.
To better understand this condition, the scientists investigated whether chemical modifications to the genetic RNA molecule could be altered and play a pathogenetic role in PKD. Specifically, they looked at the activity of Mettl3, the enzyme that carries out this methylation reaction. In three mouse models of PKD, they found that Mettl3 activity and resulting m6A levels were significantly higher than in healthy animals without the condition. The same was true for kidney samples from PKD patients compared to healthy kidney samples. Further investigation showed that in mouse models, Mettl3 activity increased before the first kidney cysts appeared, suggesting that it could be an early event for the disease. When the researchers genetically engineered healthy mice to produce excessive production of Mettl3, the animals developed small kidney cysts, even if they did not have PKD gene mutations.
In contrast, the genetic closure of Mettl3 in PKD models significantly slowed cyst growth, suggesting that the enzyme plays a key role in disease progression. training. When the researchers cultured kidney tissue in Petri dishes with varying concentrations of methionine, the cysts increased with higher concentrations. The researchers saw an opposite phenomenon when PKD mice were fed a low-methionine diet – these animals had less severe PKD. Mechanisms behind this have not been studied, but may involve several aspect of either methionine itself or methylation metabolism (enzymatic) on DNA and proteins. Scientists point out that the findings have two important implications. First, it may be possible to partially control PKD with a vegan or vegetarian diet, as methionine is found mostly in meat and fish. Second, the identification of chemicals that interfere with Mettl3 activity can lead to new drugs to treat this condition.
But hopes also open for another kidney condition of which even less is known compared to genetic renal polycystosis. Nephronophthisis (NPH; literally “nephronic destruction”) is a kidney disease that primarily affects children. NPH is inherited in an autosomal recessive pattern and, although rare, is the most common genetic cause of kidney failure in children. The clinical diagnosis of NPH in adults is problematic because the clinical, radiological and histological features are not specific. The extrarenal features are also minor in adults. Since management includes kidney transplantation and genetic counseling, accurate early diagnosis is essential. Recent genetic studies have shown that NPH can also occur in adults resulting in end-stage renal disease (ESRD). However, there are only a few case reports and no cohort studies, possibly due to rarity and diagnostic difficulties.
Now, for the first time, researchers from Tokyo Medical and Dental University have studied a number of adults with NPH and have highlighted clinical, genetic and pathological features that could help confirm this difficult diagnosis. Currently, molecular genetic testing is the only practical method to clinically diagnose NPH. However, with over 25 genes identified, Sanger sequencing (one piece of DNA at a time) is tedious and obviously time-consuming; it’s an old method. Comprehensive mutation analysis is therefore required using Next Generation Sequencing (NGS) capable of sequencing millions of fragments. Unfortunately, NGS is expensive and still has limited availability. Scientists, hailing from top medical institutions across Japan, then aimed to investigate the genetic background of adult nephronophthisis and evaluate the clinical features and pathological changes in these patients.
The research team studied 18 adult-onset NPH patients suspected of having kidney biopsy using state-of-the-art tools such as low-vacuum scanning electron microscopy and acquisition-based sequencing. They analyzed 69 genes associated with kidney disease and compared patients with and without mutations. Seven of their patients had mutations that cause NPH; they were relatively young although not significantly different in classical pathological findings. Interestingly, however, a duplication of a thick tubular basement membrane (TBM) was observed in many more tubules in these genetically proven patients. Researchers believe that the fact that this duplication is specific to adult-onset NPH is significant. The number of tubules showing this pathological change has potential as a diagnostic criterion for adult NPH.
Finally, they noted that older patients are unlikely to have pathogenic mutations; this could be a new diagnostic marker, although comprehensive tests on a target group of associated genes remain necessary.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Ramalingam H et al. Cell Metabolism 2021 Apr 9.
Fujimaru T et al. Kidney Int Reports 2021 Apr 22.
Lakhia R et al. JCI Insight. 2020 Apr; 5(7):e133785.
Watanabe S et al. Clin Case Rep 2019; 7(2):336-39.