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Abstract: TH-PO209

Repeated Doses of Cisplatin (Cis)-Induced Renal Failure Is Associated With Increased Intestinal Permeability and Glucose Intolerance

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ghosh, Siddhartha S., Virginia Commonwealth University, Richmond, Virginia, United States
  • Bu, Sarah, Virginia Commonwealth University, Richmond, Virginia, United States
  • Gipson, Graham Thomas, Virginia Commonwealth University, Richmond, Virginia, United States
  • Gehr, Todd W., Virginia Commonwealth University, Richmond, Virginia, United States
Background

Repeated doses of Cis have been shown to cause CKD. We show that Cis-induced renal failure can also cause glucose and insulin intolerance, and increased intestinal permeability, in addition to inflammation. We further show that sodium butyrate (NaB), a protector of the intestinal barrier improved renal function, glucose tolerance, and inflammation.

Methods

FVBn mice (n=5) were divided into Control (saline), Cis group (7 mg/kg cisplatin ip) every week for 4 weeks. Cis+NaB (7 mg/kg Cis+ NaB 400 mg/kg/day). Euthanized 8 weeks after the last Cisplatin injection. Glucose and insulin tolerance tests (GTT & ITT) were done 2 weeks and 1 week before sacrifice. Oral FITC dextran was used to assess intestinal permeability, 2 hours before sacrifice collected blood was analyzed for FITC and for renal function. Urine, kidney and colon were also harvested. Inflammatory cytokines TNFα, IL6, and ILβ of the kidney and colon were measured by QPCR and the results were further confirmed by western blots in the kidney. Colonic mucin was stained.

Results

As shown in the table there was deterioration of renal function, glucose tolerance, and intestinal permeability with Cis that was corrected by NaB. TNFα, IL6 and IL1β in the colon of cisplatin group were 2 to 3fold higher than control (p<0.05) that was significantly lowered by butyrate. Both qPCR and western showed increased cytokines in the kidney (3 to 7fold p<0.050). Butyrate reduced TNFα and IL6 but not IL-1β. A significant loss of mucin was observed in the colon of cisplatin treated mice which was abrogated with butyrate.

Conclusion

Cis-mediated inflammation and loss of colonic mucin likely changed intestinal permeability and caused hyperglycemia and renal dysfunction. Butyrate, a colonic nutrient, and HDAC inhibitor prevented intestinal permeability and inflammation resulting in improved renal function, GTT, and ITT.

 Control (C)CisCis+NaB
BUN
(mg/dl)
62.2±4177±72 (a)91±11 (b)
Creatinine
(mg/dl)
0.3±0.31.7±0.8 (a)0.8±0.2 (b)
Urinary Protein
/Creatinine ratio
105±9119±2 (a)107±6 **
GTT
(mg*min/dl)
18626±492537943±4760 (a)27762±1735 (b, c)
ITT
(mg.min/dl)
5200±5776354±115 (a)5151±201 (b)
Plasma FITC
(ng/ul)
0.6±0.11.3±.0.3 (a)0.9±.17 (b)

Control vs Cis =a (p<0.05); Cis vs Cis+NaB=b (p<0.05); Control vs Cis+NaB=c (p<0.05) ** Cis vs Cis+NaB (p=0.051)