by The University of Hong Kong

Credit: Molecular Therapy (2024). DOI: 10.1016/j.ymthe.2024.11.018

A research team from the School of Chinese Medicine in the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) has discovered that C-reactive protein (CRP) can exacerbate kidney inflammation caused by diabetes, also known as diabetic kidney disease (DKD), through a Smad3-NLRP3 inflammasome-dependent mechanism. Therefore, future research targeting CRP or the Smad3-NLRP3 mechanism may provide new treatment directions for DKD.

The findings were published in the journal Molecular Therapy and featured as the cover story of the issue. The team is currently screening active compounds in traditional Chinese medicine that inhibit NLRP3 activation to find new treatments to reduce inflammation in patients with DKD.

Currently, more than 500 million people worldwide suffer from diabetes, and the number of diabetic patients is expected to exceed 600 million by 2030 and 700 million by 2045. DKD is one of the most common complications of diabetes and a leading cause of end-stage kidney disease, placing a significant financial burden on patients and economic burden on society.

CRP is an inflammatory protein whose level rises rapidly when the body undergoes an inflammatory response, making it a commonly used clinical marker for inflammation. Recent studies have shown that CRP exacerbates kidney inflammation and fibrosis through the TGF-β/Smad3 signaling pathway, worsening DKD. The activation of the NLRP3 inflammasome is a key factor driving kidney inflammation, but it remains unclear whether CRP enhances inflammation in DKD through the NLRP3 inflammasome pathway.

The research team analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2010, focusing on the participants’ blood test results. They compared levels of CRP (an inflammatory marker) and hemoglobin A1c (a measure of blood glucose control) and calculated the glomerular filtration rate (a measure of kidney function).

The study found that higher CRP levels in patients with DKD were associated with lower glomerular filtration rates, indicating reduced kidney function. This suggests a clear negative linear relationship between CRP levels and kidney health in DKD patients.

The team then created a special diabetic mouse model containing the human CRP gene. By analyzing RNA from the kidneys of these mice, they identified a gene called NLRP3, which is associated with DKD. Further research showed that the NLRP3 inflammatory signaling pathway was significantly activated in the kidneys of these mice, and CRP also promoted the activation of another protein called Smad3.

To verify the role of Smad3, the team bred diabetic mice lacking the Smad3 gene. They found that when the Smad3 gene was removed, the activation of the NLRP3 inflammatory signaling pathway was significantly reduced. This indicates that Smad3 plays a key role in activating the NLRP3 inflammatory signaling pathway.

The team further discovered that activated Smad3 (called P-Smad3) can bind to the promoter region of the NLRP3 gene, thereby activating NLRP3 expression. The team also identified the exact binding site. This research reveals the important roles of Smad3 and NLRP3 in DKD, offering new directions for future treatments.

Professor Chen Haiyong, Assistant Professor in the School of Chinese Medicine, HKUMed, who led the study, stated, “Although previous studies identified various typical and atypical mechanisms of NLRP3 inflammasome activation, our findings demonstrate the direct signaling mechanism by which CRP activates the NLRP3 inflammasome in DKD.”

The team noted that blocking CRP and inhibiting the Smad3 signaling mechanism could effectively suppress inflammation in DKD, providing alternative therapeutic targets.

Professor Chen added, “We will continue our efforts to screen active compounds in traditional Chinese medicine that inhibit NLRP3 activation, with the aim of treating frequent kidney inflammation in DKD patients and preventing further deterioration of kidney function.”

More information: Yifan Wang et al, C-reactive protein promotes diabetic kidney disease via Smad3-mediated NLRP3 inflammasome activation, Molecular Therapy (2024). DOI: 10.1016/j.ymthe.2024.11.018

Journal information:Molecular Therapy

Provided by The University of Hong Kong

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