The role of KIM-1-mediated proximal tubule injury in the pathogenesis of diabetic nephropathy
Increasing evidence suggests that the kidney tubule plays an important role, and that tubulointerstitial injury may contribute to glomerular changes in diabetes (1). We have focused on the roles of kidney injury-related molecules, mainly surface receptors of renal tubular epithelia, in both acute and chronic tubular degeneration, inflammation and fibrosis. Kidney injury molecule–1 (KIM-1) was identified originally in our laboratory as an early marker of proximal tubule injury (2) We recently reported that KIM-1 acts as a novel epithelial phosphatidylserine and scavenger receptor, and that its levels in urine are a very good predictor of the progression of albuminuria in patients with type 1 diabetes (3,4). These findings indicate that proximal tubule injury and dysfunction hold a critical role in the progression of diabetic nephropathy (DN). This is further supported by other recent findings from our laboratory that: 1. injured proximal tubule cells undergo cell cycle arrest in G2M phase and assume a pro-inflammatory and pro-fibrotic secretory phenotype as a consequence of maladaptative response (5), and 2. repetitive targeted proximal tubule injury alone triggers interstitial fibrosis and secondary glomerulosclerosis in a non-diabetic mouse model (6).
We have found that proximal tubular KIM-1 expression and urinary KIM-1 levels are increased in an animal model of DN and correlate with the degree of tubulointerstitial and glomerular pathology. KIM-1 functions as a receptor for endocytosis of advanced glycation endproducts (AGEs) and oxidized low-density lipoproteins (oxLDLs), both of which are known to be elevated in patients with diabetes, and triggers pro-inflammatory and pro-fibrotic responses. A diabetic mouse with a deletion of the mucin domain of KIM-1 (KIM-1mucin) is protected from proximal tubular uptake of AGEs and oxLDLs, albuminuria, and development of DN. These results demonstrate an important role for KIM-1 in the pathogenesis of early proximal tubule cell injury in diabetes, and identify KIM-1 as a novel pharmacological target for the prevention and treatment of DN.
We will investigate next the following three questions:
- 1-What are the mechanisms by which KIM-1-mediated uptake of AGEs and oxLDLs induces tubular injury and fibrosis in DN?
- 2-How does selective modification of various properties of the KIM-1 molecule modulate KIM-1-mediated tubular injury and fibrosis and alter the course of DN?
- 3-Can targeted proximal tubule injury alone accelerate typical pathological features of diabetic kidney disease including the glomerular lesions typical of DN?
1. Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol. 2012 Sep;32(5):452-62 PMCID:3595316
2. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998 Feb 13;273(7):4135-42.
3. Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest. 2008 May;118(5):1657-68. PMCID: PMC2293335
4. Vishal S. Vaidya, Josef S. Ozer, Dieterle Frank, Fitz B. Collings, Victoria Ramirez, Sean Troth, Nagaraja Muniappa, Douglas Thudium, David Gerhold, Daniel J. Holder, Norma A. Bobadilla, Estelle Marrer, Elias Perentes, André Cordier, Jacky Vonderscher, Gérard Maurer, Peter L. Goering, Frank D. Sistare, Joseph V. Bonventre. Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies. Nat Biotechnol. 2010; 28(5): 478–485. PMCID: PMC2885849
5. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010 May;16(5):535-43, 1p following 143. PMCID: PMC3928013
6. Grgic I, Campanholle G, Bijol V, Wang C, Sabbisetti VS, Ichimura T, et al. Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int. 2012 Jul;82(2):172-83. PMCID: PMC3480325