The Kidney Specific Protein myo-Inositol Oxygenase, a Potential Biomarker for Diabetic Nephropathy

Abstract

Background/Aims: Renal tubular injury plays an important role in the progression of diabetic nephropathy (DN). However, there is a lack of specific biomarkers for tubular damage in incipient DN. We have evaluated the role of myo-inositol oxygenase (MIOX) in the tubular injury of DN, but whether it could serve as a new biomarker for the early diagnosis of DN is unclear. Methods: Ninety patients with type 2 diabetes mellitus (T2DM) were divided into normoalbuminuria, microalbuminuria and macroalbuminuria groups. Fifteen patients from the last group were pathologically diagnosed as type 2 DN (T2DN), and fifteen patients with minimal change disease served as a control group. The expression of MIOX and silent information regulator 1 (Sirt1) in renal biopsies was determined by immunohistochemistry (IHC), and serum/urine MIOX, Sirt1, KIM-1 and NGAL were measured using enzyme-linked immunosorbent assays (ELISAs). Spearman’s correlation and multiple regression analyses were carried out for statistical analyses. Results: Compared with the controls, MIOX expression was significantly increased in the renal tissues of T2DN patients, and was positively correlated with tubulointerstitial lesions and renal ROS production but inversely correlated with Sirt1 expression. In addition, the serum and urine MIOX were significantly increased and gradually elevated with the increasing of UACR. Interestingly, elevated MIOX levels in serum and urine were found in diabetic patients without early signs of glomerular damage (normoalbuminuric group). Further multivariate regression analysis showed that sMIOX and uMIOX correlated significantly with HbA1c, serum creatinine and logUACR, respectively. Conclusion: These data indicate that increased MIOX expression in the kidney contributes to tubular damage in DN. The concentration of MIOX in the serum and urine may serve as a new biomarker for the early diagnosis of DN.

Kidney-based in vivo model for drug-induced nephrotoxicity testing

“…Furthermore, it has been clinically found that diabetes, sepsis and ischemia/reperfusion increase sensitivity to AKI 43 – 45 . Miox expression significantly increased in patients with type 2 diabetes mellitus and correlated with tubulointerstitial lesiony 27 . Importantly, in diabetic patients without early signs of glomerular damage, serum and urine MIOX levels have increased.…”

“…Urinary myo-inositol and Miox tissue expression were associated with the initial estimated GFR in focal segmental glomerulosclerosis patients 24 . Recent studies further found that Miox is a kidney-specific proximal tubule protein that increased in the serum of animal with AKI or diabetic nephropathy and the plasma of patients with severe AKI patients or type 2 diabetes mellitus 25 – 27 . In addition, cadmium-induced toxicity in mice kidney significantly increased Miox levels in the tubular cells 28 , and the Miox concentration in the serum and urine may negatively reflect the rental function 29 .…”

Review of potential biomarkers of inflammation and kidney injury in diabetic kidney disease

“…In determining biomarkers with most potential in DKD, several factors require consideration, one involves the way participants are categorised within cross‐sectional studies. Most studies have stratified participants into stages of albuminuria as markers of DKD, namely, microalbuminuria and/or macroalbuminuria 40–42,44,51–57,59,63,64,105,106,108–111,113–116,119–124,127,129,130 . However, the use of albuminuria is contentious given that progression in the albuminuric stage is not a necessary prerequisite for the development of DKD 4,14 .…”

“…This emphasises the inaccuracies that exist with eGFR as a marker of kidney function. 133 Other kidney injury biomarkers that were investigated in crosssectional studies but infrequently cited include, urine megalin, uromodulin, immunoglobulins, netrin-1, cyclophilin-A, myo-inositol oxygenase and glypican-5 107,114,119,[126][127][128][129][130][131] (Table 6). Further research would assist with validation of these markers.…”

“…Most studies have stratified participants into stages of albuminuria as markers of DKD, namely, microalbuminuria and/or macroalbuminuria. [40][41][42]44,[51][52][53][54][55][56][57]59,63,64,105,106,[108][109][110][111][113][114][115][116][119][120][121][122][123][124]127,129,130 However, the use of albuminuria is contentious given that progression in the albuminuric stage is not a necessary prerequisite for the development of DKD. 4,14 Hence, biomarkers associated with albuminuria do not capture progressive DKD without albuminuria.…”