Linagliptin Limits High Glucose Induced Conversion of Latent to Active TGFß through Interaction with CIM6PR and Limits Renal Tubulointerstitial Fibronectin.
BACKGROUND
In addition to lowering blood glucose in patients with type 2 diabetes mellitus, dipeptidyl peptidase 4 (DPP4) inhibitors have been shown to be antifibrotic. We have previously shown that cation independent mannose-6-phosphate receptor (CIM6PR) facilitates the conversion of latent to active transforming growth factor β1 (GFß1) in renal proximal tubular cells (PTCs) and linagliptin (a DPP4 inhibitor) reduced this conversion with downstream reduction in fibronectin transcription.


OBJECTIVE
We wanted to demonstrate that linagliptin reduces high glucose induced interaction between membrane bound DPP4 and CIM6PR in vitro and demonstrate reduction in active TGFß mediated downstream effects in a rodent model of type 1 diabetic nephropathy independent of high glycaemic levels.


METHODS
We used human kidney 2 (HK2) cells and endothelial nitric oxide synthase knock out mice to explore the mechanism and antifibrotic potential of linagliptin independent of glucose lowering. Using a proximity ligation assay, we show that CIM6PR and DPP4 interaction was increased by high glucose and reduced by linagliptin and excess mannose-6-phosphate (M6P) confirming that linagliptin is operating through an M6P-dependent mechanism. In vivo studies confirmed these TGFß1 pathway related changes and showed reduced fibronectin, phosphorylated smad2 and phosphorylated smad2/3 (pSmad2/3) with an associated trend towards reduction in tubular atrophy, which was independent of glucose lowering. No reduction in albuminuria, glomerulosclerotic index or cortical collagen deposition was observed.


CONCLUSIONS
Linagliptin inhibits activation of TGFß1 through a M6P dependent mechanism. However this in isolation is not sufficient to reverse the multifactorial nature of diabetic nephropathy.
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, 2065, Australia.
Muralikrishna
M
Gangadharan Komala
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, 2065, Australia.
Simon
S
Gross
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, 2065, Australia.
Amgad
A
Zaky
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, 2065, Australia.
Carol
C
Pollock
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, 2065, Australia.
Usha
U
Panchapakesan
D000818:Animals; D002460:Cell Line; D005353:Fibronectins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D000069476:Linagliptin / Q000494:pharmacology*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D005353:Fibronectins; D016212:Transforming Growth Factor beta; D000069476:Linagliptin; D005947:Glucose