Structure of the human PKD1-PKD2 complex
Mutations in two genes, PKD1 and PKD2, account for most cases of autosomal dominant polycystic kidney disease, one of the most common monogenetic disorders. Here we report the 3.6-angstrom cryo–electron microscopy structure of truncated human PKD1-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel (VGIC) fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential (TRP) channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical TRP channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the VGIC, a five–transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. The PKD1-PKD2 complex structure establishes a framework for dissecting the function and disease mechanisms of the PKD proteins.
Conclusion: Urine biomarkers of podocytes injury were significantly higher in ADPKD patients even in the early stage of the disease than in the control group. It should be clarified whether these biomarkers can provide new prognostic parameters for disease surveillance.Nephron
Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.Am J Nephrol 2019;49:487 –493
In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. METHODS: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3',5'-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. RESULTS: Consistent with the development ...
Nature Reviews Nephrology, Published online: 22 May 2019; doi:10.1038/s41581-019-0155-2This Consensus Statement developed on behalf of the Network for Early Onset Cystic Kidney Disease provides guidance on counselling, diagnosing and monitoring children with autosomal dominant polycystic kidney disease based on current evidence and a multi-stakeholder discussion of ethical issues.
We report one such case of carnitine palmitoyltransferase II deficiency (CPT2) deficiency that manifested as isolated echogenic kidneys with early neonatal demise where successful early prenatal diagnosis was possible in the subsequent pregnancy.
We report that KO of MCP-1 in these mice increased survival. Surprisingly, however, there was no significant difference in renal macrophage concentration, nor was there improvement in cystic disease or kidney function. Examination of cpk mice revealed cardiac hypertrophy, and measurement of ECG parameters revealed cardiac repolarization abnormalities compared to non-cystic mice. MCP-1 KO did not affect the number of cardiac macrophages nor did it alleviate the cardiac aberrancies. However, MCP-1 KO did prevent development of pulmonary edema, which occurred in cpk mice, and promoted a decreased resting heart rate and an inc...
New England Journal of Medicine,Volume 380, Issue 20, Page 1954-1954, May 2019.
Condition: Autosomal Dominant Polycystic Kidney Disease (ADPKD) Intervention: Drug: Tolvaptan Sponsor: Korea Otsuka Pharmaceutical Co., Ltd. Not yet recruiting
CONCLUSIONS: Both height-adjusted total cyst number and height-adjusted total cyst volume increased exponentially and more than doubled over 14.23 years of follow-up. Compared with PKD2 plus no mutation detected, PKD1 was associated with a greater cyst number and volume at a given age, but no significant difference in the rate of growth. PMID: 31088850 [PubMed - as supplied by publisher]
Condition: Polycystic Kidney Diseases Intervention: Other: Dialysis Sponsor: CHU de Reims Completed