Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Zhiwei Qiu1, Jinzhao He1, Guangying Shao1

  • 1State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.

Insights

Obacunone effectively inhibits cyst growth in autosomal dominant polycystic kidney disease (ADPKD) models. This natural compound acts as a NRF2 activator, offering a promising new therapeutic avenue for ADPKD treatment.

Area of Science:

  • Nephrology
  • Pharmacology
  • Molecular Biology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder causing kidney failure.
  • Current ADPKD treatments are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify a potential therapeutic drug for ADPKD from a natural antioxidant compound library.

Main Methods:

  • Virtual screening and various cyst models (MDCK, embryonic kidney, PKD mouse) were employed.
  • In vitro and in vivo experiments assessed obacunone's efficacy.
  • Western blot and morphological analyses elucidated the underlying molecular mechanisms.

Main Results:

  • Obacunone significantly inhibited cyst formation and expansion in both in vitro and in vivo models.
  • Obacunone functions as a NRF2 activator, suppressing lipid peroxidation via GPX4 upregulation.
  • It also restrained cell proliferation by downregulating mTOR and MAPK signaling pathways.

Conclusions:

  • Obacunone demonstrates potent renal cyst inhibitory effects in ADPKD.
  • This compound shows potential for development into an effective therapeutic agent for ADPKD.

Related Concept Videos

Nephrons01:10

Nephrons

The kidneys are intricate organs with millions of working units known as nephrons. Each nephron features two major structures: the renal corpuscle, which facilitates blood plasma filtration, and the renal tubule, which handles the glomerular filtrate. Blood supply is directly linked to the nephrons. The renal corpuscle consists of the glomerulus, a capillary network, and the Bowman's capsule, a double-walled epithelial structure that encases the glomerulus. The filtering of blood plasma...
3.7K
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.0K
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.2K
Renal Drug Excretion: Tubular Secretion01:28

Renal Drug Excretion: Tubular Secretion

Active tubular secretion is a robust, energy-demanding process that utilizes carrier systems to transport drugs into renal tubules. The active renal secretion systems include the organic anion transporter (OAT) for weak acids and the organic cation transporter (OCT) for weak bases. Structurally similar drugs can compete for the same transporter, potentially leading to drug accumulation and toxicity. However, this principle can be exploited therapeutically. One example is probenecid (Probalan),...
401
Renal Drug Excretion: Tubular Reabsorption01:25

Renal Drug Excretion: Tubular Reabsorption

Tubular reabsorption, a process occurring post-glomerular filtration of drugs in the renal tubule, is a critical determinant of drug half-life. During the process of renal excretion, as the glomerular filtrate progresses to the distal convoluted tubule (DCT), drugs that are highly permeable, lipophilic, and nonionized undergo passive reabsorption from the tubular fluid into the surrounding peritubular capillaries. This reabsorption process restricts their elimination through the kidneys. This...
405