Kidney Week

Abstract: SA-PO520

ManNAc Improves Nephropathy but Worsens Hyperglycemia in Diabetic Rats by Inducing O-GlcNAcylation

Session Information

• Diabetic Kidney Disease: Basic - III
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Kharlyngdoh, Joubert Banjop, Rush University Medical Center, Chicago, Illinois, United States

Joubert Banjop Kharlyngdoh,

• Del Nogal Avila, Maria, Rush University Medical Center, Chicago, Illinois, United States

Maria Del Nogal Avila,

• Das, Ranjan, Rush University Medical Center, Chicago, Illinois, United States

Ranjan Das,

• Donoro blazquez, Hector, Rush University Medical Center, Chicago, Illinois, United States

Hector Donoro blazquez,

• Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States

Eduardo Molina-Jijon,

• Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States

Lionel C. Clement,

• Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States

Camille E. Mace,

• Avila-Casado, Carmen, University Health Network, University of Toronto, Toronto, Ontario, Canada

Carmen Avila-Casado,

• Chugh, Sumant S., Rush University Medical Center, Chicago, Illinois, United States

Sumant S. Chugh,

Background

The sialylation inducing compound N-acetyl Mannosamine (ManNAc) improved renal function in Nephrotic syndrome rats model (Clement LC et al Nature Medicine Jan 2011). We compared the overall efficacy and side effect profile of ManNAc with another sialylation inducing compound GDT01 in diabetic rats.

Methods

MManNAc study: 5 month old ZDF male rats (n = 5 rats / group) were treated for 5 months with tap water or ManNAc in drinking water. Changes in proteinuria, BUN, creatinine, hyperglycemia and histology were assessed.
GDT01 study: 5 month old male ZSF1 rats (n = 6 rats / group) were treated with plain tap water or GDT-01 over a period of 7 months. Same parameters as above were assessed.
Muscle protein content of the diabetogenic sugar O-GlcNAc was assessed using 1D and 2D gel Western blots for both studies. O-GlcNAcylation occurs at the same amino acid residues as O- glycosylation and phosphorylation.

Results

ManNAc reduces proteinuria in ZDF rats significantly (P<0.05, P<0.01) when compared to water control group. The blood glucose level in ManNAc treated animals was also significantly (P<0.05) increased. GDT01 treated rats showed a significant reduction in proteinuria (P<0.05 to P<0.01) without any increase in blood glucose levels. Analysis of BUN and creatinine levels showed no significant changes in the ManNAc study, but improved in the treated group in the GDT01 study ( P<0.05, P<0.01). In addition, renal histology was remarkably better in GDT01 treated rats.
Assessment of O-GlcNAc showed increased levels in skeletal muscle in ManNAc treated rats, but no change in GDT01 treatment. This suggests that shuttling of ManNAc into O-GlcNAc induces diabetogenic changes, that negate otherwise potentially beneficial effects in treating diabetic nephropathy. It is likely that this phenomenon is noted also in non-diabetic rats, suggesting “diabetes like” side effect profile in the absence of diabetes.

Conclusion

The sialic acid precursor ManNAc is diabetogenic and should be avoided as a sialylation inducing agent. GDT01 improves diabetic CKD without being diabetogenic, and remains the preferred sialylation inducing agent

Funding

• NIDDK Support