Introduction: Diabetic kidney disease (DKD) is a major complication of diabetes, which is associated with sclerotic glomerular disease and poor perfusion. Therefore, improving the renal perfusion may help to halt or reverse the kidney injury. We want to investigate whether transplanting genetically modified EPC by silencing apoptosis gene p53 may promote vasculogenesis and improve renal perfusion. We also wanted to compare p53shEPC with another possible cell therapy such as mesenchymal stromal cell (MSC) (unmodified).
Method: Hyperglycemia and proteinuria in STZ-induced type1-diabetic mice were confirmed at 8 weeks post STZ, followed by transplantation of 0.3 million p53shEPCs, NullEPCs, mouse MSC (mMSC) or saline (control) under each kidney capsule. Urine protein and plasma creatinine were estimated weekly. Perfusion was measured by laser Doppler at sacrifice at week 4 followed by renal histology and qRTPCR.
Results: Reduction of proteinuria was observed in p53shEPC transplantation group compared to null (1.3 fold). Plasma creatinine of p53sh-EPCs group was less than nullEPC (2.7 fold) but similar to MSC transplanted animals (1.5 fold). Increased perfusion was noted p53sh-EPC group compared to NullEPC, MSC and saline (1.2, 2.4 and 3.0 fold respectively). Markers for angiogenesis, such as eNOS (2.6, 1.6 fold respectively) and VEGFA (1.2, 1.5 fold respectively) increased more with post p53shEPC transplantation compared to nullEPC and MSC. We noted heart rate (HR) reduction post p53shEPCs transplantation compared to null whereas HR actually increased in mMSC transplanted mice. Kidney histology following Isolectin-β4 staining showed significant improvement in sclerosed glomerular vascular tufts, with p53shEPC delivery, compared to null, MSC and saline.
Conclusion: Transplantation of p53sh-EPC improved proteinuria, perfusion, and vascular gene mRNAs compared to NullEPCs, MSCs and saline. Modified EPC transplantation may have a prominent cell therapy role in DKD.
N. Kundu: None. L.D. Asico: None. J. Banerjee: Employee; Self; Osiris Therapeutics, Inc. P.A. Jose: None. S. Sen: None.
American Heart Association