Urinary Excretion of Kidney Aquaporins as Possible Diagnostic Biomarker of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is a microangiopathic complication of diabetes mellitus (DM) affecting one-third of diabetic patients. The large variability in the clinical presentation of renal involvement in patients with DM makes kidney biopsy a prerequisite for a correct diagnosis. However, renal biopsy is an invasive procedure associated with risk of major complications. Numerous studies aimed to identify a noninvasive biomarker of DN but, so far, none of these is considered to be sufficiently specific and sensitive. Water channel aquaporins (AQPs), expressed at the plasma membrane of epithelial tubular cells, are often dysregulated during DN. In this work, we analyzed the urine excretion of AQP5 and AQP2 (uAQP5 and uAQP2), via exosomes, in 35 diabetic patients: 12 normoalbuminuric with normal renal function (DM), 11 with proteinuric nondiabetic nephropathy (NDN), and 12 with histological diagnosis and classification of DN. ELISA and WB analysis independently showed that uAQP5 was significantly increased in DN patients. Interestingly, linear regression analysis showed a positive correlation between uAQP5 and the histological class of DN. The same analysis, focusing on uAQP2, showed comparable results. Taken together, these data suggest a possible use of AQP5 and AQP2 as novel noninvasive biomarkers to help in classifying the clinical stage of DN.

Streptozotocin induces alpha-2u globulin nephropathy in male rats during the end-stage of diabetic kidney disease

“…Diabetic nephropathy is a microangiopathic complication present in one-third of diabetes mellitus patients [18]. It has been claimed that dysregulation of the water channel membrane protein "aquaporin; AQP" in the kidney plays an important role in the pathogenesis of several kidney diseases including diabetic nephropathy [18][19][20]. Eight AQPs, AQP-1-7 and − 11, are expressed in the kidney to maintain normal urine concentration [20].…”

“…Upregulation of glomerular AQP-1 is found in all forms of human renal diseases, probably due to compensation for losing cellular integrity [19]. Upregulation of AQP-2 and − 5 is closely related to the progression of diabetic nephropathy in diabetic patients and are good candidates to use for diagnosis [18,24]. Recently, Go and Zhang also reported that an increase in AQP-5 in patients with diabetic nephropathy is independently associated with a reduction in the glomerular filtration rate [25].…”

Roles for Exosome in Various Kidney Diseases and Disorders

“…The data showed that urinary exosomal bikunin precursor and histone-lysine N-methyltransferase were increased, whereas voltage-dependent anion-selective channel protein 1 was decreased, in DN patients and might lead to the improve diagnostics and monitoring of DN (Zubiri et al, 2014). Later, the increased levels of AQP-2 and AQP-5 were detected in urinary exosomes derived from DN patients, suggesting that these proteins may serve as the non-invasive biomarkers for diagnosis of DN (Rossi et al, 2017). In a subsequent transcriptomics study using miRNAs microarrays, urinary exosomal miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR-371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p, and miR-2861 were increased, whereas miR-30d-5p and miR-30e-5p were decreased in type 2 DN patients (Delic et al, 2016).…”

Urinary Extracellular Vesicle

“…Rossi et al . [ 5 ] analyzed the AQP2 and AQP5 (uAQP5 and uAQP2) excreted in urine in 35 patients: 12 diabetic patients with normoalbuminuria and normal renal function, 11 with proteinuria nondiabetic nephropathy, and 12 with histological diagnosis and classification of DKD. Interestingly, the enzyme-linked immunosorbent assay (ELISA) and Western blot analysis independently showed that uAQP5 was significantly increased in DKD patients.…”

“…[ 3 ] It is also well-known that some diabetic patients could develop renal failure without preexisting albuminuria. [ 5 ] Given increased prevalence and significant socioeconomic burden caused by DKD, the noninvasive and more accurate early diagnostic biomarkers will be needed to improve the quality of patient life and reduce its impact on healthcare.…”