Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

Abstract

Aims/hypothesis We examined the link between altered gap junctional communication and renal haemodynamic abnormalities in diabetes in studies performed on Zucker lean (ZL) and the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. Methods The abundance of connexin (Cx) 37, 40 and 43 was assessed by western blot and immunohistochemistry. Renal haemodynamics was characterised with GAP peptides, which are Cx mimetics, to inhibit gap junctions as a probe in both strains. Results ZDF rats exhibited higher plasma glucose, 8-epiprostaglandin F2α excretion, renal plasma flow and GFR than ZL rats. In ZDF rat kidney phosphorylation of Cx43 was enhanced compared with that in ZL rats. Immunohistochemical study revealed that the density of abundance of Cx37 in renin-secreting cells was significantly reduced in ZDF rats. Although renal autoregulation was markedly impaired in ZDF rats, it was preserved in ZL rats. GAP27 for Cx37,43 and for Cx40 impaired renal autoregulation in ZL rats, but failed to induce further alterations in renal autoregulation in ZDF rats. Conclusions/interpretation Our findings indicate that ZDF rats have glomerular hyperfiltration with impaired autoregulation. They also demonstrate enhanced phosphorylation of Cxs and reduced production of Cxs in ZDF rat kidney, especially of Cx37 in renin-secreting cells. Finally, our data suggest that an impairment of gap junctional communication in juxtaglomerular apparatus plays a role in altered renal autoregulation in diabetes.

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

“…Renal renin and angiotensinogen contents increase in diabetes [43]. Although plasma renin activity is similar in Zucker diabetic fatty and Zucker lean rats [13], preliminary data from the same group show elevated intrarenal ANG II content in Zucker diabetic fatty rats, which is appropriately reduced by high salt intake [44]. In 2K1C clipped kidney, the renin content shows an early massive rise, but later decreases to control levels, while that of the non-clipped kidney becomes vanishingly small [45].…”

“…Reduced efficiency of autoregulation increases susceptibility to, and rate of progression of, hypertensive nephropathy [9][10][11]. It is often considered that autoregulation is impaired in diabetes, and diabetic hyperfiltration has been attributed to enhanced transmission of systemic pressure to glomeruli [2,12,13]. However, efficient autoregulation has also been reported in diabetes [7,[14][15][16], and the literature has been described as contradictory [14,17].…”

TGFβ modulates cell-to-cell communication in early epithelial-to-mesenchymal transition

“…Reduced cell adhesion, cell coupling and cell-to-cell communication have profound effects on overall integrity and function of the proximal tubule, and altered GJIC and renal haemodynamics have recently been reported in a Zucker fatty rat model of type2 diabetes [49]. In the current study, we concede that our in vitro data provide a minimalistic model of the early events in EMT and thus recommend caution in translating these novel findings to the in vivo situation, where the multifactorial molecular pathology of renal fibrosis may modify responses.…”

Elucidating mechanisms underlying altered renal autoregulation in diabetes

“…Kuroki et al (15) demonstrated that high glucose enhanced phosphorylation of Cxs, impairing gap junction functions (15). Using ZDF rats lacking leptin receptors (45), we have shown that reduced expression and enhanced phosphorylation of Cxs in the JGA relate to suppressing TGF signal transduction, resulting in almost complete abolition of renal autoregulation (32). Previous data indicated that P 2 receptor inhibition resulted in partial attenuation of autoregulation, including TGF (30).…”