Impact of periodontitis on diabetic complications

Background + Aims

• Diabetic nephropathy is the leading cause of chronic kidney disease and often progresses despite good control of blood sugar, blood pressure and cholesterol.
• Periodontitis (chronic gum disease) is common in diabetes and has been linked to worse kidney outcomes, but the underlying mechanism has been unclear.
• This study aimed to:
  • Identify how periodontitis accelerates diabetic nephropathy, and to test whether targeting a candidate pathway can prevent kidney damage.

Materials + Methods

• Diabetic KK-Aʸ mice (a genetic model of type 2 diabetes) and non-diabetic C57BL/6 mice received ligature-induced periodontitis ( a silk thread tied around the molars to trigger gum inflammation) or no ligature.
• Kidney function was assessed with UACR (urinary albumin-to-creatinine ratio – a marker of glomerular leakage) and BUN (blood urea nitrogen), plus histology of glomeruli.
• RNA sequencing of isolated glomeruli was used to find genes altered by periodontitis; candidate proteins were validated.
• An haematopoietic prostaglandin D synthase (HPGDS) inhibitor (HQL-79, 30 mg/kg orally, x1/daily for 3 weeks) was tested therapeutically.
  • HPGDS is an enzyme that produces prostaglandin D2 (PGD2). PGD2 is a lipid-based signalling molecule involved in inflammation and immune responses.
• A small clinical cohort of 12 outpatients with type 2 diabetes at Kyushu University Hospital had urinary HPGDS, UACR, eGFR (estimated glomerular filtration rate – a measure of kidney function), HbA1c (average blood sugar) and periodontal measurements collected.

Results

• Periodontitis significantly worsened kidney function in diabetic mice with higher UACR, higher urinary albumin, and higher BUN, without changing blood sugar.
• Glomerular pathology worsened with evidence of larger glomeruli, more mesangial expansion (thickening of the supportive tissue), more fibrosis, more CD68+ macrophage infiltration, and reduced tight-junction proteins ZO-1 and Occludin.
• RNA-seq identified HPGDS as the standout candidate.
• Glomerular HPGDS was ~200-fold higher in diabetic mice than in controls, and periodontitis raised it a further ~1.8-fold. Glomerular PGD2 rose in parallel.
• HQL-79 (an HPGDS inhibitor) normalised glomerular PGD2, reduced UACR and BUN, lessened fibrosis, inflammation and macrophage infiltration, and restored tight-junction gene expression, without affecting blood glucose, body weight or alveolar bone loss.
• In the 12-patient cohort, urinary HPGDS/creatinine correlated significantly with periodontal pocket depth (r = 0.657, p = 0.028) and showed trends with UACR (r = 0.539, p = 0.075) and HbA1c (r = 0.557, p = 0.064). Pocket depth also correlated with UACR (r = 0.678, p = 0.019).

Limitations