Direct evidence of proximal tubular proliferation in early diabetic nephropathy

Abstract

Kidney hypertrophy is a common clinical feature in patients with diabetes and is associated with poor renal outcomes. Initial cell proliferation followed by cellular hypertrophy are considered the responsible mechanisms for diabetic kidney hypertrophy. However, whether similar responses against hyperglycemia continue in the chronic phase in diabetes is unclear. We performed lineage tracing analysis of proximal tubular epithelia using novel type 2 diabetic mice with a tamoxifen-inducible proximal tubule-specific fluorescent reporter. Clonal analysis of proximal tubular epithelia demonstrated that the labeled epithelia proliferated in type 2 diabetic mice. Based on the histological analysis and protein/DNA ratio of sorted labeled tubular epithelia, there was no evidence of cellular hypertrophy in type 2 diabetic mice. Lineage tracing and histological analyses of streptozocin-induced type 1 diabetes also revealed that cellular proliferation occurs in the chronic phase of type 1 diabetes induction. According to our study, epithelial proliferation accompanied by SGLT2 upregulation, rather than cellular hypertrophy, predominantly occurs in the hypertrophic kidney in both type 1 and type 2 diabetes. An increased number of SGLT2+ tubular epithelia may be an adaptive response against hyperglycemia, and linked to the hyper-reabsorption of sodium and glucose observed in type 2 diabetes patients.

Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

“…People with diabetes typically have higher blood glucose in comparison to normal people, and to balance homeostasis, more glucose needs to be reabsorbed to ensure the absence of glycosuria, which primarily depends on the upregulation of SGLTs and GLUTs ( 53 – 55 ). When comparing the diabetic rats to the normal ones, the mRNA of SGLT2 and SGLT1 was increased by 36% and 20%, respectively ( 56 ).…”

“…At the onset of diabetes, kidneys grow due to expanded nephron size; renal hypertrophy occurs mainly in the cortex of the diabetic kidney and is linked to subsequent proximal tubular hyperreabsorption ( 25 , 55 ). Uehara−Watanabe et al.…”

“…Uehara−Watanabe et al. showed that the kidney weight, proximal tubules, and glomeruli size were significantly higher in streptozotocin-induced rats ( 55 ). Greater glomerular volume and glomerular basement membrane (GBM) width were also demonstrated in patients with early DKD ( 68 ).…”

Clinical Study of α 2-MG, PCX, AFU, RBP-4 and CysC in type 2 Diabetes Mellitus and Diabetic Nephropathy

“…Currently, it is believed that renal tubules play an important role in early DN, so the exploration of biomarkers has become a hot research topic at present [29]. The molecular weight of AFU is about 270-390 kDa, and it is di cult to pass through the glomerulus.…”

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

“…To our knowledge, SGLT2 gene expression in AS of humans or animal models has not been reported; however, increased expression has been reported in tubular epithelial cells from urine of diabetic patients [ 42 ], although conflicting results have been reported in tissue samples [ 43 , 44 ]. Tubular epithelia of type 1 and type 2 diabetic mice had elevated SGLT2 levels [ 45 ], and mice fed high-fat, high-salt (HF/HS) diets were also reported to increase kidney SGLT2 gene expression, possibly in an Ang-II-dependent manner [ 46 , 47 , 48 ].…”