Immunohistochemical Expression Pattern of Mismatch Repair Genes in the Short-term Streptozotocin-induced Diabetic Rat Kidneys

Abstract

We studied the expression of mismatch repair genes (MMRs)-mutS protein homolog 2 (MSH2), PMS2, MutL homolog 1 (MLH1), and yH2AFX in diabetic rat kidneys. Streptozotocin-induced diabetes mellitus type 1 rat model (DM1) was used. Renal samples were collected 2 weeks and 2 months after DM1 induction and immunohistochemical expression of MMR genes in the renal cortex was analyzed. Diabetic animals showed lower MSH2 and higher yH2AFX kidney expression both 2 weeks and 2 months after DM1 induction. MLH1 expression significantly increased 2 weeks after DM1 induction (P < 0.0001). The most substantial differences were observed in the period 2 weeks after induction, with lower MSH2 and higher MLH1 expression in the proximal convoluted tubules and distal convoluted tubules (DCT) of diabetic animals (P < 0.001). yH2AFX expression significantly increased in the DCT of diabetic animals at both time points (P < 0.001; P < 0.01). PMS2 expression changed only in the glomeruli, where it significantly decreased 2 months after DM1 induction (P < 0.05). We concluded that the most substantial changes in renal expression of MMRs are happening already 2 weeks after diabetes induction, predominantly in the proximal convoluted tubules and DCT. Moreover, DCT could have a critical role in the pathophysiology of diabetic nephropathy (DN) and might be a future therapeutic target in this condition. The obtained results point to the MMRs as a potential factor in the development and progression of DN, as well as the possible link between DN and renal carcinogenesis.

Altered Expression of EMT-Related Factors Snail, Wnt4, and Notch2 in the Short-Term Streptozotocin-Induced Diabetic Rat Kidneys

“…Previously, glomerular basement membrane damage with subsequent microalbuminuria has been recognized as a synonym for diabetic kidney disease, while tubular cell dysfunction has not received adequate attention in this condition so far. These results accentuate the role of the Snail signaling pathway in the long-term tubular EMT process and are compatible with our previous reports that have pointed out the relevance of the proximal and distal tubular epithelial cell changes in the development of DN [ 5 ]. Additionally, Kai-Yun Fang et al have noticed the statistically significant up-regulation of the Snail mRNA and protein expression in diabetic rat renal tubules, while a time-dependent down-regulation of Snail expression in the insulin-treated rat kidneys [ 26 ].…”

“…On the other hand, proximal convoluted tubule (PCT) dysfunction occurs early in DN development and may precede glomerular damage [ 4 ]. Moreover, recent studies have revealed that the distal convoluted tubular (DCT) cells might be the primary site of damage in DN [ 5 ].…”

Diabetes mellitus impacts on expression of DNA mismatch repair protein PMS2 and tumor microenvironment in pancreatic ductal adenocarcinoma

“…Generally, oxidative stress has been found to play an essential role in diabetes and the pathogenesis of diabetic complications 22,27,28 . However, in streptozotocin‐induced diabetic rat kidneys, PMS2 expression was suppressed only in the glomeruli, but not in the tubules 29 . This might indicate that PMS2 expression can be changed in a tissue specific manner, possibly due to the differences in oxidative stress sensitivity.…”

Potential Influence of Age and Diabetes Mellitus Type 1 on MSH2 (MutS homolog 2) Expression in a Rat Kidney Tissue

“…Similarly, diabetes mellitus is a complex pathological process that can be only modeled in vivo in its full complexity [ 18 ]. Since both ageing, diabetes mellitus and MSH2 deficiency have been linked, to a certain extent, with neoplastic and non-neoplastic renal diseases [ 13 , 19 , 20 , 21 , 22 ], we decided to explore the influence of age and diabetes mellitus type 1, on renal MSH2 expression in an ageing diabetic rat model.…”